Don't look for "the" structure

It surprises me how often I hear students, postdocs, and even professors talk about determining the structure of a protein. A singular structure has the advantage of being relatively easy to interpret, but the cost of this is often the loss of functional data. It's easy to understand how this terminology emerges from the discipline of crystallography, which after all only works when the protein molecules adopt only a small number of conformations. Yet even when it comes to NMR, a technique that should be very sensitive to the fact of structural multiplicity, the language of researchers and the structural tools available to them are too often oriented towards the idea of a singular structure. But any representation of a protein as a single conformation is a simplification — every protein exists in multiple structural states.

Trivially, we are aware that a given polypeptide chain can adopt a number of different conformations — the "folded state" of any given polypeptide chain covers only a tiny sliver of the possible conformational space. A protein that is "unfolded" occupies not a single, well-defined state but a vast multiplicity of states, and this kind of statement is not controversial because we tend to imagine unfoldedness as a messy chaotic jumble of conformations. The reality is less cut-and-dried: although unfolded proteins may have no regular structure, many still have a propensity to form particular secondary structures or interactions. The reality of denatured proteins is that they have a complex and varied energy landscape, not an array of possible structures that all have roughly equivalent energy. The flipside of the popular view is that the a protein's native state draws down to a sharp energy well, and this conception is also misguided.

The most dramatic counterexamples to the idea of a neat, punctate energy well come from proteins that adopt several different folds in the native state. One relevant case is lymphotactin, which freely interconverts between an α/β monomer and an all-β dimer under physiological conditions. Lymphotactin may be unusual, but the principal message from that study is one that ought be paid attention to in others, particularly when the protein in question has functional conformational diversity. Consider α-synuclein, a protein implicated in Parkinson's disease. In the presence of some detergent micelles this protein is known to take on an α-helical hairpin structure, with two helices laying down on the charged surface of the lipid headgroup. In solution, however, it seems to take on a number of different forms, and may interact with true lipid bilayers in a completely different way than it interacts with micelles. For proteins that interconvert between several different physiologically-relevant folds, one is never pursuing the structure, but rather a structure.

Of course, we don't expect most proteins or domains to regularly adopt alternate overall folds. However, reorientations of domains or monomers is a relatively common behavior, and one that poses a sticky challenge for structural biologists because incidental properties of a particular arrangement may bias our experiments towards observing it. A minor member of the ensemble, if it has favorable packing geometry, may exclusively populate a crystal. Similarly, NMR experiments to determine domain arrangement via residual dipolar couplings must always be undertaken with an eye to ensuring that interactions with the aligning media do not bias the results. No single structure of adenylate kinase can instruct us about its catalytic cycle, and structures of the unbound state do not capture the reality that the protein continues to open and close in the absence of ligand. Single structures do not capture motions of domains or monomers relative to each other and that often means an incomplete understanding of function.

Domain motions are also an overly dramatic example, because simpler rearrangements of the backbone take place in many proteins, even when regular secondary structures are evident. Fluctuations of the main chain play a functional role in several proteins — as, for instance, in the flaps of the HIV protease. Additionally, rearrangements of the backbone have a significant role in signaling, as in NtrC, which I'll talk about more in two weeks. Proteins where the main chain rearranges in response to ligand binding or post-translational modification generally cannot be described by a single structure.

Even if the backbone is rigid, every protein will have flexibility in the side chains of its amino acids. One of course expects to see this kind of behavior in side chains on the surface of a protein, where it is usually dismissed as irrelevant. However, we also know that side chains can rotate and move in the core of a protein, and that on some protein surfaces they can undergo coherent rearrangements. I'll talk a bit more about the functional relevance of side-chain motions next Thursday. For now, suffice to say that side chain rotations cannot be so easily ignored and sometimes have functional effects. Structural studies that do not capture these rotations may be missing something important.

My point here is not that single structures are stupid or useless. A structure can be very informative about about a protein's function, and often has great power to explain the effects of mutations and ligands. However, we should not mislead ourselves into thinking that any single structure will have all the answers, or indeed any of them. Every protein is a constantly interconverting ensemble of structures, and there are many layers of structural diversity within that ensemble, reaching from whole fold rearrangements to "mere" side-chain adjustments. Determining the structure of a protein is not a coherent goal for a research program. The successful structural biology study will characterize the conformation and energy of key, functionally-relevant members of the protein's structural ensemble and identify the pathways between them.

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Chosen at birth

Last post, I mentioned that the tendency to choose segregation as a means to solve problems was a feature of many societies in the world of Dragon Age. Another, related motif appearing in many Thedan societies is the existence of a rigidly-defined social order in which a person's status and even his occupation are set at the moment of birth. To varying degrees this kind of social rigidity appears in almost every social group in the game (except the elves). Through its dialogue and plot, Dragon Age: Origins repudiates these systems, but in its mechanics it supports them.

The most obvious example of social rigidity in the game is the caste system of the dwarves of Orzammar, which assigns occupation and status to a person based on that of the same-gendered parent. Caste systems in general serve to stratify and divide society, but this one is notable for its lack of mobility. Even marriage and childbirth do not result in an individual's movement from one caste to another, although a low-caste woman may be adopted into a noble family if she gives birth to a noble's son. Otherwise, a dwarf's status and occupation is chosen for him by his birth.

In a somewhat ironic twist, the society of the qunari giants in many ways seems to resemble that of the dwarves. The game's main qunari character, Sten, is often reticent about his own past, but is happy to share his views on the appropriate role of women and other people who don't know their "place". To him, it is mystifying that farmers want to be merchants, merchants want to be warriors, and warriors want to be nobles. Moreover, he simply cannot process the idea of women who fight in battle, even though the game's most effective recruitable characters are all female. Qunari society is not explained in great detail, but Sten makes it evident that it is one of rigid divisions and roles.

The people of Ferelden also have a very stratified society, on the bottom of which reside the elves, who have been freed from slavery but not oppression. They are held in their position by ethnic violence — characters within the Denerim alienage point out that elves who move out often end up dead, their homes burned by humans. Above them is the bulk of humanity, and among the commoners it appears that upward mobility is at least possible, if not a regular occurrence. It is important to realize, though, that the human commoners also have a ceiling on their aspirations, for they will not become nobles. Teyrn Loghain is the exception that proves the rule — the breathless astonishment of the common soldiers for his elevation to nobility borders on disbelief. The treatment of his rise to power as a freakish occurrence speaks eloquently to the existence of a vast gulf between the two tiers of human society.

The game actually seems quite ambivalent about the social rigidity repeated throughout Thedas. In its fundamental structure, the story argues against strict stratification — the social and economic positions of the various origins are quite diverse, but they all end up in the same honored place as a mighty gray warden. Sten's views on social and gender roles are easily punctured by a female protagonist, and mercilessly mocked by Morrigan whenever she gets a chance. On several occasions it is made clear that the dwarven caste system is slowly killing the culture that gave birth to it. From all this it would seem that this game, like the culture from which it emerged, explicitly rejects the validity of rigid social divisions.

The mechanics of the game, however, buy into the qunari ideals because Dragon Age features firm class boundaries and rigid character builds. A character cannot mix the skills of a mage and a warrior or rogue, and a warrior-archer cannot adopt the Ranger specialization reserved for rogues. A character chooses an occupation and is then locked into it and can never become anything different. He cannot even become a different type of his own character class. A player who fully develops a rogue archer and finds he does not like the build has no option for addressing his mistake other than replaying the game entirely because there is no way to respec.

The character's real "birth" into the game world occurs when the player designs him, choosing an origin and a class. From this moment forward, his occupation is set. If the player later finds himself unhappy with his character's lot, there is no remedy but to start over with a new "life". In this respect, the mechanics of the game resemble the defined and restrictive social systems that appear so frequently in its world. Although many of the characters praise the idea of breaking the mold, and the game itself appears to argue against institutions like the dwarven caste system, any such message is undercut by the practical reality that the game actually employs such a system itself.

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Out of sight, out of mind

Playing Dragon Age gave me a relatively frequent sense of déjà vu. Although the game portrays a number of different nations and societies, there are recurrent features that speak to underlying ideas about the psychology of its inhabitants. One such motif is the tendency for its denizens to solve their problems through segregation. At several levels, the people of the continent of Thedas like to resolve issues by pushing problematic groups into isolated areas and pretending, as much as possible, that they no longer exist.

The most obvious manifestation of the segregation impulse appears in the form of the elven alienage seen in Denerim. Here, as in countless ethnic ghettos, the impoverished elves are made to live together in squalor. Walls surround the alienage, keeping the elves in and humans out. Some elves express thanks for this function, and why should they not? When humans appear in the alienage they typically intend violence. The wandering Dalish elves, by contrast, separate themselves from what they perceive as the contaminating influence of humanity through constant motion. Notably, the solution chosen by the humans for the elves of the city is the same as that which the free-roaming elves have chosen for themselves. Though the city elves are segregated in their homes, and the Dalish by their homelessness, the net effect is the same.

Similarly, the Thedans respond to the social and religious challenge of magic by isolating the Circle of Magi in their own remote tower in the center of a lake. There they live under constant guard by church knights, for fear that they will take up forbidden practices or fall victim to demons. While the chief religion of Ferelden teaches only that magic should serve man rather than control him, this idea seems to translate to the masses and the clergy as a warning that magic, and mages, are sinful and dangerous. While magic might be of great use to the people, the Chantry prefers to separate the mages from the population, with the upshot that their normality and helpfulness pose no challenge to the popular conception. Although its mythology suggests that mages were the originators of the darkspawn and the Blight, Dragon Age is not as ambivalent towards the circle's isolation as it is the elves': the oppressive segregation of mages gives rise to two of the game's tragedies, by fueling Uldred's political ambitions and by causing Connor to be left vulnerable to demonic manipulation.

Strategic challenges are also met by the Thedan segregation impulse. A "Blight" begins when the darkspawn awaken an archdemon and spread onto the surface to attack the humans living there. When the archdemon is slain, the darkspawn retreat underground and victory is declared. For the surface-dwellers, this may be so, but when the Darkspawn retreat, it is only to renew an ongoing war with the dwarves who live underground. To them, the Blight is actually a brief reprieve. Here the disadvantage inherent in the segregation approach is obvious: pursuing the darkspawn using the full force of the assembled army could conceivably hamstring future Blights and would at least buy the dwarves some time to rebuild their numbers and society. Yet the surface-dwellers persist in the belief that once the darkspawn are back in their place, the crisis has ended. By ignoring the darkspawn who have been pushed back, the Thedans ensure the continued strength of their enemies, and the continued weakening of their allies, the dwarves.

Yet the dwarves, too, feel the segregation impulse. Their society is built on a rigid caste system, but a significant fraction of their population doesn't belong to any caste and therefore "doesn't exist". These individuals, who are not even allowed to join the regular army, live in a crumbling old section of the city, as rife with poverty and squalor as the alienage of the elves. In contrast to the alienage, however, the castless dwarves have formed powerful criminal organizations. Through the usual means — theft, gambling, extortion, smuggling — these enterprises allow these bottom-rung dwarves to damage the rest of their society. Again, the attempted segregation is an abject failure — disastrous to both the castless and those lucky enough to belong to a caste. The dwarves cling to this failed system nonetheless, because they seemingly cannot imagine any other.

What is lacking from Dragon Age is any sense that the people of Thedas are significantly conscious of the shortcomings of these systems. Certainly they are least cognizant of the most dangerous — their failure to continue the fight against the darkspawn once the horde retreats. Yet each of these systems is social poison, and while isolated individuals speak out against them, there is no organized effort to correct the mistakes. Defeating the darkspawn horde merely removes an immediate threat to a society headed towards an inevitable catastrophe brought on by the dividedness it has chosen to embrace. Maybe that's why it's "dark" fantasy.

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A few things

I promise there will be actual content in essay form later this week, but I have to kick the week off with some housekeeping. Some of this is bad, and some of it is good (or I hope it's good).

Bad news first: I've been getting pretty regular comment spam on this blog for about a month now, at a rate of about one post every half day or so. I don't know why anyone's bothering — most of the posts affected are at least half a year old — but it's still pretty irritating to click back to the blog every day to delete internet pharmacy ads written in badly formatted bbcode. Blogger doesn't give me a lot of options for dealing with this, and I'm not in the mood to migrate to some other platform. So as a first step I am turning on moderation for all posts more than 90 days old. The only kind of comment I will refuse is an obvious advertisement, but comments will obviously show up slowly on those posts. My other options are to block anonymous comments, which I definitely will not do, or to use a CAPTCHA, which I find to be annoying and have evidence is only moderately effective. Hopefully this will resolve the issue.

On the good side, my friend Ben Abraham, proprietor of the SLRC blog and organizer of Critical Distance, is going to be visiting GDC. Michael Abbott and David Carlton have already gotten him a pass, but since Ben is in Australia and GDC is in America, there's a rather expensive plane ticket to deal with. On the right side of the blog you can see a little widget for donating money to help cover the cost of that flight. I'd appreciate it if you could spare a few bucks to give him a hand.

If giving money to Ben doesn't sound like something you want to do, then I hope you'll find space in your budget to give a few dollars to Penny Arcade's annual Child's Play charity drive. Child's Play buys toys, books, and games for children's hospitals throughout the world to help make the lives of children with serious illnesses much less miserable. I spent a lot of time in hospitals myself as a kid, and the only parts of those stays that didn't suck terribly was the time I got to spend getting my ass kicked by the original Legend of Zelda. You can donate money, plain and simple, or you can choose your local children's hospital and buy something from their Amazon wish list. There are items on those lists that cost as little as $10 and will make a big improvement in what is usually a horrible experience, so please donate something if you can.

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The uncertainty principle

Although it uses conventional horror tropes, Condemned: Criminal Origins takes an unusual approach for a survival horror game. Survival horror often generates tension through resource scarcity, limiting the player's ability to fight or heal himself, but because of its melee combat focus Condemned is necessarily limited in this respect. The relatively plentiful checkpoints mean that the player usually isn't punished excessively for failure. Yet Condemned is a frightening, tense game because it artfully keeps the player from knowing what is coming next.

Condemned has a significant advantage when it comes to generating fear because of its visceral combat. While a few guns can be found in almost every level of the game, its hero Ethan Thomas can't carry ammunition for any of them. As a result, he is forced to improvise melee weapons from the environment, and fight his enemies up close and personal. Moreover, he's not fighting fantastic creatures, but ordinary people who have taken on (in most cases) a subtly monstrous aspect. The close quarters and melee brutality make the combat intrinsically frightening, but if that were all that Condemned had going for it, it would not be a truly scary game.

Video games pose a special problem with regard to creating fear because any game is a system that can be mastered. If the designer wishes to evoke a fear response through an attack on the avatar, he must contend with the player's ability to manipulate a game's combat systems. If the player becomes proficient at fighting off the enemies, or lowers the difficulty to compensate for his incompetence, then the onset of a fight stops being frightening and starts becoming a problem to be solved. Similarly, if a cue or activity is known to precede a fight loses its power to develop fear. These moments cease to be tense and instead become a time where the player prepares himself for a battle he knows is coming. Knowing that a fight is about to happen lets the player feel in control of moments where he is meant to feel vulnerable. To be frightening, a game must re-weight the power relationship in favor of the designer, rather than the player.

Condemned presents just this kind of activity in the form of crime scene investigation tools that Ethan must use to track down the serial killer who has framed him. The player often must use the tools in order to find vital clues, but Ethan cannot hold one of these gadgets and a weapon simultaneously. Thus, every use of an evidence-collection tool leaves Ethan vulnerable to attack. In any number of games this would form the basis of a recurring sequence: see clue → collect evidence → get assaulted. The player would enter the state just described, in which starting to collect evidence would signify the onset of a combat sequence and allow the player to feel control. Instead, the developers of Condemned chose to attack the player during the course of evidence collection only occasionally. Sometimes Ethan gets attacked while he collects evidence, and sometimes he does not. The player cannot develop mastery because these sequences have ambiguous outcomes.

Condemned plays with this idea in other ways as well. Environmental sounds sometimes signify an imminent attack, and sometimes do not. In one level, some mannequins turn into enemies and others, often indistinguishable, don't. The levels occasionally rearrange themselves, without regular signifiers. Condemned avoids predictability, and this denies power to the player.

The finest articulation of the skillful design that went into Condemned comes in its penultimate chapter, in which Ethan must search the (apparently) empty house of the serial killer for clues. The killer has written trails of words that lead to important spots, but these can only be seen if the player uses Ethan's UV lamp. The whole house becomes an evidence collection routine, but the developers resist the urge to have enemies burst out of every door and window as Ethan searches. The occasional attacks they employ instead support the tension of the sequence without letting the player view it as a combat routine. This level is so memorable in part because of the exquisite suspense it generates.

The most interesting thing about choosing to attack at only some of these junctures is that it doesn't come at any cost. From studies of conditioning, we know that using a variable schedule of positive or negative reinforcement (i.e. not reinforcing every time) is no less effective at generating a desired response than continuous reinforcement. In fact, research has shown that conditioned responses created using variable reinforcement are more resistant to extinction than those created with continuous reinforcement. By associating the fear of a surprise attack with just some of these evidence-collection routines, the developers guarantee tension in all of them, without granting the player any feeling of power over the game.

Condemned ultimately falls down because of its last level, an uninteresting romp across a farm, beating down mutant hillbillies on your way to a dull and conventional final boss. Up to that point, however, Condemned cleverly steals power from the player by avoiding routine. Because the player can never be certain when an attack is coming, the intrinsic fright generated by the game's brutal combat is never diluted by the player's mastery. The player's uncertainty perpetuates his fear.

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Capsule: Nostalgia

Final Status: Story and most low-level side quests complete.

Put This on Your Box: At last, a game that ignores Britain's long history of brutal aboriginal repression!

Most Intriguing Idea: Evoking the 19th-century adventure novel in a game.

Best Design Decision: Near-ideal implementation of turn-based combat in the ground battles.

Worst Design Decision: Incredibly unbalanced and tedious airship battles.

Summary: Nostalgia unapologetically grabs for dated JRPG tropes, and for the most part succeeds in creating a pleasant experience. We have a chipper sword-wielding teen with spiky blond hair, a demure teenage girl with magic powers and amnesia, and two spunky orphans, all out to save the world from... well, it's a JRPG, so the story doesn't make much sense anyway. This time the hash is made with an inappropriate fusion of Norse and Greek mythologies, if you're keeping score. Battles proceed using a turn-based system similar to Final Fantasy X. The system is sharp, transparent, and perfectly executed (graphically appealing too: this is a quality game). On the ground, the difficulty curve is quite gentle and the battles are mostly easy. Even if you never take a single side-quest you will probably be perfectly prepared (or even over-leveled) when the end of the main story comes. The aerial battles are another matter: they are brutally difficult and often unwinnable. Players will frequently find themselves unable to either hit the enemy ship at all, or to escape. When victory can be achieved, it can sometimes take up to ten minutes to whittle down the massive life bars of enemy airships. Even at low altitudes, relatively frequent encounters with enemies that totally outclass the player's own Maverick airship occur well into the game, forcing frequent reloads. Nostalgia also appears to have the warm fuzzies for the British Imperium, but not a lot of time to spend on acknowledging what that meant for people who weren't white. To an extent this is excusable because the whole goal here is to evoke the feel of a Victorian adventure novel (the hero's parents have separate bedrooms), but it adds to the sense that this game is out of date — in this case, by at least a century.

If you can't say something nice... When it stays on the ground, Nostalgia is a fun little romp evoking pleasant memories of JRPGs past.

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Capsule: Mario & Luigi: Bowser's Inside Story

Final Status: Story finished.

Put this on your box: I HAVE CHORTLES!

Most intriguing idea: Leveling up your arch-nemesis to defeat your other arch-nemesis.

Best design decision: Constantly layering something new and interesting on the core mechanics.

Worst design decision: The unbalanced dodge mechanic and the tedious temporary invincibility in the boss fights.

Summary: Mario & Luigi: Bowser's Inside Story follows an established pattern for the Super Mario role-playing games. It combines light platforming action with turn-based battles that are supplemented with timing-based action to improve damage or defense. This has worked before and it works here, creating a perfectly competent RPG where Mario and Luigi roll around in Bowser's guts, powering up the big spiky turtle so he can take down the ludicrous Fawful, who has conquered both the Mushroom Kingdom and Bowser's domain. The gameplay is mostly solid, but the dodge mechanic is unbalanced. If you figure out the dodge for an attack, you'll never take a point of damage, but if you don't figure out what to do or the proper timing for it you will die constantly. Earlier RPGs in this series mostly used the dodge to reduce rather than eliminate damage, and that would have been a wiser choice here, as the ability to escape harm completely seems to have encouraged the designers to make enemy attacks very powerful. In addition, many of the bosses have some kind of invulnerability (Fawful, for instance, is effectively invincible for five turns at a time), which makes fighting them fairly tedious. On the plus side, every area inside of Bowser seems to have its own interesting twist, making sure the platforming never gets old, and powering him up uses some nifty rhythm games that I rather liked. The writing mostly works well, especially when you encounter the loopy dialogue of characters like Fawful, Sakon, or the doctor. Unfortunately, Bowser himself is pretty one-note, although his tough-love attitude towards his subordinates, and their adulation towards him, can be pretty funny. After a while, though, he wears thin, and there's so much of his dialogue in the game that it gets a bit tiresome. For me, the game overstayed its welcome a bit, but despite some minor design hiccups it's a high-quality experience that delivers both humor and gameplay depth.

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Blog of the Round Table: The denouement of the rings

The role-playing game, as a genre, owes much to the imagination of J.R.R. Tolkien. The same could be said for much of the fantasy genre in film and literature as well, but the diversity of approaches in these media reflects intricate linkages to multiple concepts of fantasy and folklore. Role-playing games, which build lengthy, epic storylines in fantasy worlds populated by multiple sentient races, follow in the footsteps of Tolkien's magnum opus. In terms of the time investment and the breadth of the imagined world, many RPGs are quite similar to The Lord of the Rings, but while that trilogy keeps going for several chapters after the climactic fight with the forces of Sauron, a game typically stops dead after its most intense battle, with ill effects for both character arcs and the closure of the story. Since they've taken so much from Tolkien already, perhaps games could look to his last chapters to find inspiration for gameplay beyond the climactic fight.

Let's begin by considering the case of Eowyn and Faramir, two characters who are slowly falling in love during the late phases of The Return of the King. Their stories effectively end with a scene in which Faramir confesses his love and asks Eowyn to consider him. It's not particularly realistic, but RPGs that have a particular focus on relationships and the use of conversation trees (Mass Effect, for instance) could take a cue from this. A relationship that has developed slowly over the course of the game could be realized in the aftermath of the final battle. Obviously, you could make this dependent on successful navigation of a conversation tree. In a game like Mass Effect that links conversational proficiency with actions and attitudes during the game, making this tree impossible for a particular alignment could be a way to emphasize the personal cost of the decisions that have been made.

As part of his closing arc, Aragorn, who is concerned about his ability to maintain Gondor in the future, is led by Gandalf into the mountains, where he finds a seedling offspring of the sacred tree Nimloth, symbolizing the rebirth of the nation. This is, essentially, the novelization of a fetch quest, and a gameplay denouement of this kind would require some extra elbow grease to be emotionally effective. However, if an appropriate symbol is developed throughout a game, then a mission to retrieve that symbol could be a good way to bring closure to an epic RPG. Having defeated the great enemy, you find an object that matters personally to the characters and implies hope for the future.

The hobbits have the most elaborate denouement, in the form of their journey back to the Shire, and the elimination of the forces endangering it. This approach has several advantages, which are shared between trilogy and game. Firstly, many interesting characters are developed at the beginning of the story who must necessarily be left behind when the journey at the core of it begins. Returning to those characters reminds the player (or reader) of the things that seized his interest back when he started. Additionally, seeing the central characters in the presence of the initial supporting cast again provides a yardstick for measuring their increase in maturity, confidence, and power. Because RPGs, particularly of the Japanese variety, are often concerned with the maturation of the hero as a parallel to his leveling up, this is an effective way to reflect on the implications of the game as a whole.

The triviality of the destruction of the forces of the Shire displays the newfound strength and leadership of the hobbits of the Fellowship, but it also points out another possibility for closing out a story. For some reason it is typical to have the final boss or the leader of the opposing forces be some immensely powerful warrior, but this need not be the case. You could set up a story where a relatively weak king is supported by an army of incredibly powerful soldiers. Defeating his minions could be tough, but the king himself could be a trivial boss. The climactic battle could come much earlier than the final fight, with the last battle in the game serving as an expression of a new power relationship in the world. Something along these lines occurred near the end of Final Fantasy X, where the real climax of that game is the battle against Yunalesca and the bosses within Sin constitute various moments of farewell, although admittedly some of these fights are not easy.

The final phase of The Lord of the Rings that I want to draw attention to is the departure of the ringbearers from the Grey Havens, symbolizing their passage into the next life. Characters in RPGs often die as a part of the story, or occasionally (as in the Fire Emblem games) perish permanently if they fall in battle. A journey to carry their spirits to the next world, or simply to return their bodies to their home villages, could provide gameplay that puts those losses in context. One could also make the bodies a physical burden in some way, making this journey more difficult in a Lonesome Dove kind of way.

Of course, these various approaches could also be combined in various ways to provide a closing chapter that follows the climactic boss. My point here is not that The Lord of the Rings is the apotheosis of effective denouement in fantasy storytelling. However, the way it ties up its character arcs contains a number of ideas for developing a more interesting closing to an RPG story than just a cutscene followed by a credit scroll. Extending the gameplay beyond the climactic boss offers the opportunity to put a satisfying cap on the character and world development, and thus make the whole story a richer and more rewarding experience.

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Not quite legendary

A music fan, particularly a fan of a musical style that has acquired additional cultural trappings, asserts individuality by membership in a group. The contradiction has given rise to familiar parent-teenager fight scenes in a hundred tired family dramedies. Though the story stays the same from decade to decade, the music changes, and understanding the fan means understanding not just the sense of community brought by any fandom, but also the vital energy of the musical style itself. The engine of Tim Schafer's Brütal Legend rumbles with the energy of heavy metal. Unfortunately, it never really roars to life.

More than enough has been said about the world of Brütal Legend, a land of heavy metal album imagery brought to life. The aesthetic is somewhat divergent, because metal has a fascination with both medieval fantasy and modern road machines. What unifies these interests is the desire for power and recognition, as articulated through archaic battle ideals and contemporary engine tuning. The game's protagonist, Eddie Riggs, plays into this idea because although he is an extremely capable roadie, he is forced to use his talents in unrecognized service to a particularly irritating faux-metal group of recent vintage. When he is transported to the world of real metal he has the opportunity not only to use his talents in service to his preferred kind of rock, but also to put down the forces that corrupted it in his life.

Although the world of Brütal Legend has dozens of opportunities for side missions, their repetitious nature means that the most interesting gameplay lies in the linear main story. Many of the encounters in that quest involve "Stage Battles", where Riggs commands a rock army fueled by the adulation of merch-hungry fans. This came as a surprise to me, as the demo had led me to believe that the game would be more in the vein of a third-person action/adventure. And, in all honesty, my utter incompetence at the stage battles eventually caused me to be thankful that I could change the difficulty mid-game. Still, the stage battles gave me the impression that they were meant to generate the feeling of individual and group empowerment that lies at the core of the metal experience. Giving the player control of an individual leading an army of headbangers and chopper-mounted warriors creates an opportunity to charge into battle at the head of a rock'n'roll army.

In practice, however, this doesn't work out. It's not that the stage battles are completely broken, it's just that the sum of a dozen little things makes them much less fun than they should be. Ordering individual units or groups of units to attack specific points is often advantageous but too much of a chore. Figuring out where you're being attacked, or where your troops even are, is often too difficult. If you distribute your forces across several different objectives or locations you will rapidly become overwhelmed by the task of trying to command them all effectively. Even when you hook up with them, actually charging into battle with them is a tough timing trick: your allies never quite seem to keep your pace, always running a bit behind or a bit ahead.

Beyond the mechanical issues, the problem with the stage battles is that nobody is on the stage. The internal fiction of Riggs as an unappreciated roadie falls apart because everyone, including the putative leaders of the human rebellion, takes orders directly from him. Thus, the late attempt to bring the story back around to the idea of Riggs as a behind-the-scenes player rather than an acknowledged hero feels implausible and unearned, especially given that his head prominently adorns a nearby mountain. Brütal Legend has the roadie, but not the band, and you need both if you're going to have a real rock concert.

Brütal Legend doesn't hang around for long, which is fine, but it cuts off abruptly, as if in mid-story, and that is not fine. More than half of the game's missions flesh out a conflict with hair-band avatar Lionwhyte, a relatively minor player, and most of those are tutorials to one degree or another. The rest of the game concerns a series of battles with the forces of the Drowned Doom, representative of the dramatic excesses of the goth scene. Then, within moments after their defeat, the player is dropped into the final boss fight against the demon lord Doviculus, leader of the Tainted Coil. Aside from the jarring shift to fighting a new, totally unfamiliar enemy, this smash cut into the final battle sells the whole conflict with the forces of the Tainted Coil short. The danger that Lionwhyte and the Drowned Doom pose to the world, and their relationship to real-life corruptions of the "metal" ethos, are pretty clearly developed, but Doviculus and the Tainted Coil get very little of this, and none of it is experienced through play. In essence it feels like a third of the game got cut out.

The story that remains is of uneven quality. The game's early segments are tightly written, and draw humor from the plausible behavior of well-realized characters. The excesses of heavy metal imagery and modern music are played for laughs, but not in a mean-spirited way. The writers know that we know that sometimes heavy metal takes itself too seriously, and play that angle up. Then the writers go and fall into the same trap, and start to focus less on the amusing adventures of Eddie Riggs and more on the serious business of the game's plot. This would be fine, except that Brütal Legend falls firmly into the class of stories where nobody says the few obvious and reasonable words that would solve all their problems, until the buzzer goes off and it is Time To Explain The Story before the final boss battle. The sharp comedic writing of the introductory segment slowly oozes out of the script, leaving only flaccid melodrama by the end. You can laugh at that, perhaps, but not with it.

For a fan, a musical style is an important part of an individual personality, but it is also a key way of identifying with a group. You can't really capture the essence of the allure of heavy metal without incorporating both those aspects, and Brütal Legend's curious mix of play styles may well be the best way to deal with this dichotomy in a game. Unfortunately, art that addresses contradictory ideas often turns out to be contradictory in its own right, and this is the fate that befalls Brütal Legend. The third-person action never sits quite right with the tactical elements, and the advantages of the game's open world are offset by the repetitive nature of the side-missions. The writing switches from self-aware comedy to self-absorbed melodrama, much to its detriment, and the game tries unsuccessfully to set Riggs up as both roadie and frontman. Despite these problems, there is much to praise in Brütal Legend, especially its bold gameplay choices and the striking realization of heavy metal imagery in its open world. While it fails to realize its full potential, it at least succeeds in being interesting, and that alone is worthy of recognition.

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The role of dynamics in catalysis

For some enzymes, dynamics on the millisecond timescale play a critical role in catalysis. I don't think this is a particularly controversial or unclear statement, but then, I know what I mean by it. In the process of communication, however, the intended meaning sometimes gets lost or transformed. A statement that addresses an entire catalytic cycle, for instance, might be interpreted as addressing only the chemical step. This seems to have happened in a pair of papers that concern the transfer of energy from conformational rearrangements to a chemical reaction.

Consider a reaction scheme in which an enzyme loosely associates with substrates (E.S), then "closes" to form a tight, catalytically-competent complex that then undergoes a reaction with the rate k_chem:

Pisliakov et al. (1) ask whether the closing process can accelerate k_chem. They ask this question primarily because a group from Harvard University proposed that this was possible in a paper printed last year in J. Phys. Chem. B (2). In that paper, Min et al. performed some simulations suggesting that such an acceleration was at least possible, and consistent with some enzymatic data. Pisliakov et al. approach the question with simulations of the reaction of the phosphotransfer enzyme Adk with 2 ADP molecules to form ATP and AMP. As part of the catalytic cycle, the enzyme goes from an open state (PDB: 4AKE) where the ATP and AMP binding sites are exposed to solvent, to a closed state (PDB: 1ANK) where the substrates are shielded from the surrounding solution by ATP and AMP "lids" that close down over the active site.


One can, perhaps, imagine that when the enzyme closes around the substrates, some motion will occur that promotes the transfer of a phosphate group from one molecule to another. Pisliakov et al. use a three-tiered system of simulations to address the question, as a way of trying to get around the difficulty of dealing with the long timescales required. Their simulations allow them to adjust the energy barrier to match the experimental rates or accelerate the reaction so that the whole pathway can be simulated. In general, they find that conformational fluctuations do not enhance the chemical reaction rate in this system.

I have two main concerns about the science that was performed here. The first is that the energy barriers in the long-timescale experiment appear to be improperly paramaterized. In estimating these barriers for the phosphotransfer reaction in Adk, Pisliakov et al. used 260 /s as k_chem. However, although the actual reaction carried out by Adk follows an extremely complex scheme, the analysis performed by Wolf-Watz et al. utilized a simplified scheme that combined all post-association steps into a single k_cat. This is why the concordance between k_cat and k_open justifies the conclusion that lid-opening is rate-limiting. In principle, the experiments used for that paper are incapable of separating the opening and closing steps from the chemical step. Therefore we have no experimental knowledge of the phosphotransfer rate, except that it is greater than 260 /s. This perplexing error appears to have originated with Min et al., but I am surprised Warshel's group did not catch it.

This is not a major problem because the bulk of the conclusions of the experiment were drawn from a different simulation in which the energy barriers were lower, but this leads to my second concern. If the structural transition involves a very smooth and coherent rearrangement of the protein, then simply manipulating energy barriers should not result in a serious error of analysis. In reality, however, ensemble motions of protein elements are not going to be so directed or uniform. Structural rearrangements are not highly singular steps, but involve a large number of intermediates and transition states. Motions in the late stages of the structural transition that promote catalysis may well be missed by simplified models, or accelerated beyond productivity by lowering the energy barrier.

That said, I'm not particularly surprised that Pisliakov et al. find that energy from the conformational coordinate does not transfer to the chemical coordinate, nor do I disagree with the finding. Despite what Pisliakov et al. appear to believe, the papers that have come out of Dorothee's group don't argue that the millisecond motions contribute directly to the chemistry. Doro doesn't believe that for a second. Neither do I. The importance of dynamics has little to do with shoving the reaction along the chemistry coordinate, but everything to do with getting substrates bound and into a state where chemistry is possible.

Dynamics allow an enzyme to reconcile incompatible functional requirements. To efficiently function as a phosphotransfer enzyme (as opposed to a hydrolytic phosphatase), Adk must expel water from the active site during catalysis. If the active site is inaccessible to solution, however, there is no way for the substrates to diffuse into it. It is difficult to create a single, rigid fold that can accommodate both these demands, but by fluctuating between two states the problem is resolved quite easily. So yes, the dynamics are essential to catalysis, but that does not imply that the conformational and chemical energy coordinates are coupled.

More perplexing is the discussion of the hierarchy of motion, which Pisliakov et al. take to mean that nanosecond motions somehow contribute to the chemical coordinate. As I discussed when that paper was initially published, the question being addressed was whether and how motions on the fast timescale (ps-ns) in Adk were related to the slower (ms) motions of the lids. In a hierarchy of motion, fast timescale fluctuations enable or promote slow timescale dynamics. In the case of Adk, this means that nanosecond flexibility at structural hinges allow the millisecond motions of the ATP and AMP lids. It was not implied, then or since, that the nanosecond motions in question make a direct contribution to movement along the chemical coordinate. This is not to say that there are no researchers who believe that ns motions contribute to catalysis — I've previously mentioned some work on hydrogen tunneling that makes precisely this argument. In the specific case of Adk, however, the contribution of ns motions to catalysis consists entirely in their enabling of the slower ensemble motions of the nucleotide binding domains, and nobody but the Warshel group has suggested otherwise.

There is an ongoing disconnect in the literature concerning the role of dynamics in catalysis. While it is true that in many cases rates of structural transitions correlate with rates of catalysis, this does not imply that the conformational transition coordinate is linked to the chemical reaction coordinate by direct transfer of energy. It is more likely that the dynamics of the enzyme contribute to catalysis by generating reaction-competent states from reaction-incompetent states. This is not to say that dynamics cannot possibly make a contribution to phenomena such as hydrogen tunneling, but it strikes me as unlikely that motions on the millisecond timescale will contribute to a chemical coordinate. Experiments, rather than simulations, will be the ultimate test of the idea. However, in principle, this hypothesis can only be tested experimentally on enzymes where the conformational changes do not limit the chemical reaction rate. Because the rate of the chemical step is unknown in Adk, it may not be an appropriate model system for addressing this question.

1. Pisliakov, A., Cao, J., Kamerlin, S., & Warshel, A. (2009). Enzyme millisecond conformational dynamics do not catalyze the chemical step Proceedings of the National Academy of Sciences, 106 (41), 17359-17364 DOI: 10.1073/pnas.0909150106

2. Min, W., Xie, X., & Bagchi, B. (2008). Two-Dimensional Reaction Free Energy Surfaces of Catalytic Reaction: Effects of Protein Conformational Dynamics on Enzyme Catalysis The Journal of Physical Chemistry B, 112 (2), 454-466 DOI: 10.1021/jp076533c

3. Wolf-Watz, M., Thai, V., Henzler-Wildman, K., Hadjipavlou, G., Eisenmesser, E., & Kern, D. (2004). Linkage between dynamics and catalysis in a thermophilic-mesophilic enzyme pair Nature Structural & Molecular Biology, 11 (10), 945-949 DOI: 10.1038/nsmb821

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A good way to spend a day and a half

My compilation of critical writing about Grand Theft Auto IV has gone up at Critical Distance. If you have a couple of hours to devote to reading some interesting writing about the game that was supposed to change everything then hop on over and get clicking. There's a lot to read, and I ended up including a pretty diverse set of posts, from straight essays to cross-blog dialogues, to one post from Corvus' site that ended up in there because of a really interesting comment. Also, because the game appeals to such a broad swath of gamers, I made an effort to dig into gamer-oriented blogging sites like Destructoid and IGN, with uneven success. I found plenty of posts, but many of those bloggers seem to be focused on producing their own reviews rather than a focused essay. Unfortunately, while everybody has an opinion, not everyone has an interesting idea.

One idea plenty of people had was to compare GTA IV to Saints Row 2. This was an easy thought to have because the folks at Volition kept pushing the concept that GTA IV had lost the fun of the sandbox while SR2 had expanded it. I must have scrolled through a dozen bullet-point posts about why SR2 was better (this seemed to be the prevailing opinion). I probably could have hacked together a section about it, but it would have required me to accept a painful quality dip. Instead, I linked copiously to Shamus Young's compare/contrast series on the two games, which I thought did a really admirable job of examining the competing design philosophies rather than just talking about how much more fun SR2 was.

Another subject that received a lot of coverage was the phenomenally ill-advised "Ladies of Liberty City" video IGN made and then retracted. This was a real problem because the people who responded to that video generally made reasonable points about the GTA series, but often didn't do a good job of GTA IV itself, mostly because they never played it. I seriously considered a secondary post or sub-section just on this subject, because there was a lot of interesting writing about it. Unfortunately, much of it was undermined by bad fact-checking; a significant proportion of these posts, even some of the better ones, included false information about the content of the game. The sad part is that most of these essays would have been just as compelling without the misinformation. After some internal debate, I had to conclude that making the section would only lead to drama I didn't want to deal with — in particular I felt that I might end up inadvertently turning those posts into flamebait.

Aside from these, most of the other main threads of commentary made it into the sections you see in the compilation. I feel like I did a little more synthesis in this compilation than previous ones. I tried not to come down on one side or the other of any particular case, but I did try to subtly draw out ideas that were somewhat nascent in the individual essays so that they might attract new writing. One of the ideas rumbling beneath the complaints about GTA IV's heavy emphasis on linear narrative is that the gameplay of Grand Theft Auto games is inherently transgressive: the game is about breaking the rules, the boundaries, the laws. In that kind of game, ludonarrative dissonance might be created just by having a linear narrative that denies the player significant input.

I also thought there was an intriguing idea percolating in a couple of pieces that Niko lies to himself about his sociopathic tendencies using the fiction that he has no choice but to be a murderer. Niko, and Rockstar's handling of him, engendered a lot of negative reaction, but my own feeling was that they did a reasonably good job of exploring a very bad person who, like many very bad people, sees himself as a fundamentally good guy with a functional moral code. But it was also interesting to me to find that there were a number of people who took Niko at face value, and consequently tried to play the game in a way that minimized property crimes and murders. The prevailing opinion is that GTA IV requires a lot of killing, but creative players have been exploiting the game's flexibility to draw the number of murders down to a surprisingly low level. Maybe that's ganking the system, or maybe that's buying in to one part of the system over others.

Whatever you think of the Pacifist Niko Challenge as an approach to rulesets generally, it does underline one key fact about GTA IV. The rules and systems created by Rockstar North allow for a huge range of behavior, but don't really require any more violence than is typical in any other gunplay-focused game. Popular attacks on the game interpret the most extreme activities that it permits as if they were actions the game requires, often as a consequence of (proudly proclaimed) ignorance. This strikes me as a case of shooting the messenger. If we're going to get upset about what happens in a game of GTA IV, we ought to worry less about the fact that people can do horrible things in a game, and more about the fact that they actually choose to do them.

One more thing. In order to comply with the FTC I will now list everything I've received for free from a game publisher:

That is all.

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Capsule: Dead Space: Extraction

Final Status: Game completed on Normal difficulty, some levels replayed on Hard.

Put This on Your Box: It's like Civil War medicine... in space!

Most Intriguing Idea: Converting a third-person precision-shooting horror experience into a first-person precision-based rail shooter.

Best Design Decision: Working the kinesis and stasis tools into the railshooter experience.

Worst Design Decision: Long, pattern-based boss monster battles that devolved into tedious chores.

Summary: Dead Space: Extraction is a prequel to Dead Space, which I found to be more interesting than Silent Hill: Homecoming, but hit some low points that eventually drove me off. Extraction introduces this story through the experiences of six (mostly temporary) survivors of the disaster on Aegis VII and the Ishimura. Combat, as in the original, depends on the player's ability to strategically shoot off the enemies' appendages; body shots are usually ineffective. The developers attempted to bring this precision-shooting idea to the boss fights, but unfortunately that created some excessively-patterned battles that went on far too long. Those fights, and some irritatingly long mob fights aside, the gameplay was solid and the atmosphere was good. Extraction unfortunately suffers from really abysmal performance. I saw slowdown and glitches on several occasions, and the game crashed on me five times. Two of those were hard crashes that forced me to turn off the console. It's a damn shame that the game was so unstable because...

If you can't say something nice... Dead Space: Extraction really does develop some very good tense and creepy sequences. For the most part it's a solid game and a good addition (or introduction) to the Dead Space franchise.

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