The blunted blade

Japan's greatest swordsmiths, Masamune and Muramasa, were not contemporaries, but there are several legends involving both of them. One tells of a competition in which each one forged a sword and lowered the blade into a river. Masamune's sword seemed to be inert: fish swam up to it, the flowers floating in the river brushed by without harm. Muramasa's blade, in contrast, cut everything it touched. The fish were split in two, the flowers sliced to ribbons, and the very air hissed in pain as the weapon cleaved it. A passing monk saw the display and chided Muramasa, pointing out that Masamune's sword cut no undeserving thing, while Muramasa's blade killed indiscriminately. Time and legend have ascribed a bloodthirsty, evil aspect to Muramasa's swords, and it is this reputation that Muramasa: The Demon Blade aims to evoke.

Vanillaware, the creators of Muramasa, are probably best known for their 2007 role-playing game Odin Sphere, a game which was marked by a beautiful coherence of story, play, and symbolism. It would not be fair to expect another masterpiece of this quality, but I did expect the resemblance between the two games to be more than skin-deep. If you come to Muramasa looking for gorgeous 2D graphics and a fantastic score, you will not be disappointed. Unfortunately, the simplistic story and uneven design of Muramasa make it a hollow and repetitive experience.

Muramasa: The Demon Blade features two stories: that of the princess Momohime, possessed by the spirit of an evil swordsman, and that of the amnesiac ninja Kisuke. Unlike Odin Sphere, where the stories of the five main characters were intertwined in often surprising ways, these two tales have little besides backstory and a few shared characters connecting them. Moreover, the story is presented in very spare fashion, rarely offering anything more than a few lines of dialogue to explain why a particular boss must be fought or where to go next. There is no rich, textured narrative here, and as a result the game feels more like a quickie tour of Japanese folklore than a coherent story. The romance between Kisuke and Torahime is too understated, and Momohime's dedication to the reprehensible Yukinojyo is unmotivated and frankly sad.

The world of the game is, of course, feudal Japan, divided up into the provinces from the era of the Shogunate. These provinces appear in the game as a series of connected rooms (or zones, if you prefer), with some limited internal geography that must be traversed with light platforming. Sometimes these rooms are filled with enemies from the outset, in which case they can either be fought or bypassed. Random encounters also occur in these rooms, instead of in a separate battle stage, although when this happens the room no longer scrolls and the player must fight in the window onscreen at the moment of attack. Defeated enemies lose their souls, which can then be used to repair broken blades and forge new swords. Eating food (to provide "Spirit" to the character) is also necessary to forge additional weapons. The cooking element is very light, however, and most of the recipes rapidly become irrelevant because they have too small of a healing effect relative to the size of the life bar (which expands more than 50-fold over the course of the game).

The difficulty and complexity of combat, for the most part, depend entirely on the player's choice of "Muso" or "Shuro" play. In Muso mode, most battles can be won with sheer aggression, with the exception of some bosses and the random encounters I discussed in the previous post. In Shuro mode the fighting becomes more complex and tactical, although many enemies are still susceptible to a strategy of continual attack. Momohime and Kisuke have exactly the same controls and abilities, however, so the only real difference in gameplay between their respective stories is a few field enemies and the bosses. Even this disappears late in the game, when they gain the ability to fight each other's bosses. At that point the game reaches a repetitive nadir, but one that must be slogged through in order to level both of the characters up enough to wield the game's final sword and see the "true" ending. Leveling up the characters to defeat major enemies is generally unnecessary because your foes seem to scale with your level, particularly the bosses and the enemies leading up to them.

The troubling thing about these various components is that they all seem disconnected, or even opposed. The RPG elements, particularly the massive life bar, make the game's simplistic cooking system largely irrelevant. The scaling of enemies makes the leveling irrelevant, but at the same time, participation in the monotonous combat can only be justified by the need to level. The brilliant composers at Basiscape created a score that allows the battle music and field music to switch seamlessly between bars, and the battles take place without a screen swap, but the wonderful effect this has on the game's continuity is ruined by the scroll-lock and post-battle EXP screen. You run around collecting souls all game, but the story essentially ignores this grim task. Moreover, the need to do it has no real bearing on the gameplay — unless you consistently run from every battle you will have little trouble gaining the souls required to forge all the swords twenty times over by the end of the game. Muramasa is fundamentally incoherent.

I can't help but feel that Muramasa would have been better off if Vanillaware had embraced the brawler at the game's core and discarded the RPG elements (and Muso difficulty) entirely. The process of leveling up doesn't really add anything to the game, and the character development offers nothing for the player to do. Because the expanding life bar and experience screen notably interfere with other elements of the game, why not just get rid of them? Focusing the game on tactical combat, and the sword system on the selection of special attacks or abilities, would have made this a game about fighting smart rather than just about whacking things with a sword until you reach the next boss. Making Kisuke and Momohime play in noticeably different ways would also have made the game a more interesting experience.

Even those changes, though, would only somewhat ameliorate a fundamentally hollow experience. Muramasa: The Demon Blade reminds us of a famous swordsmith and his bloodthirsty blades, but the madness and viciousness thus evoked never really find their way into the gameplay or the thinly-presented story. Like its vast, fractured provinces, the various systems of the game never manage to form any coherent whole. Instead, the game comes across as a whole bunch of ideas thrown together willy-nilly and wrapped in as beautiful a package as possible. Muramasa has no secrets to reveal, no depths to plumb, no story to tell that equals its luxurious presentation. Like a ceremonial sword, it is glorious to behold, and better gazed upon than used.

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Muramasa goes to hell

Most of Muramasa: The Demon Blade is set in Japan, laid out on a map based on the provinces of its feudal period. In one act, however, the possessed princess Momohime jumps down a well in Kyoto (Yamashiro) and finds herself in a fiery underworld populated by demons. Although the game is suffused with elements from Japanese myth and folklore, this drop into a completely fantastic area represents a substantial break from the rest of the game's semi-historical motif. It represents a break in other ways as well, few of them good. Muramasa's episode in hell creates player frustration in almost every phase, to the detriment of one the game's most memorable sequences.

The stages set in hell involve a marked increase in difficulty. Most of the monsters encountered in this area are trivial little imps that have been seen all game and can be disposed of with a few strikes. Because they can launch projectile attacks if left alone, the best approach to deal with them is unbridled aggression. In the hell stages, however, these imps are accompanied by one or two hulking monsters that are very tough to kill. Not only do these oni take a great deal more damage, they also have an expanded arsenal of attacks that do significant damage to Momohime, and more importantly to her swords. Because a broken sword makes the player essentially incapable of offense or defense, these encounters can rapidly become very dangerous, and the player will spend much more time dodging attacks than is typical for a random encounter. Although the oni are vulnerable at every spot, fighting them requires a consideration for angle of attack and tactical retreat that goes beyond that needed for many of the game's bosses.

This is not an intrinsically bad thing, because the boss of this area, the Big Oni, also imposes tactical requirements that make it quite different from the preceding bosses in the game. It would have been clever to set the stage for this fight by making the oni enemies in the field have similar vulnerabilities and attacks to the big boss so that the player would be trained for the boss fight by the more ordinary encounters. Unfortunately, the oni from random encounters have only the slightest resemblance to the Big Oni in their attacks, and no similarities in vulnerability. So although they are in many ways much tougher to fight than the boss, the player takes nothing useful away from these encounters.

Irritatingly, the increased difficulty of these particular monsters does not seem to acknowledged in the experience yield from the battle. In Muramasa, the primary determinant of experience reward appears to be the monster level, which is in turn set by the player's level. This careless approach to the difficulty/reward dynamic is a characteristic flaw of Japanese RPGs, though not by any means confined to them. As Denis pointed out to me, the asymmetry between difficulty and reward appears in some Western RPGs as well. The foes introduced in Fallout 3's Broken Steel, for instance, give similar experience to their lower-level brethren, despite the steep increase in difficulty. At any rate, it's not unexpected to see this in Muramasa, though it is irritating, and it points to a larger issue I'll get into with my general critique later this week. Here, it merely accentuates the frustration of dealing with the more difficult enemies in the field, and helps turn the trip through hell, one of the least visually interesting areas in the game, into an annoying slog.

This means that the player arrives to the boss battle frustrated or even angry, which is a shame because the battle with the Big Oni is a really clever and interesting fight. The stage for combat is set by a pitch-perfect scene where Momohime convinces the Big Oni to swallow her whole, in classic trickster-hero style. The first phase of the battle then involves cutting your way out of the monster's belly, a classic epic trope that would in most other games have been played off as a cutscene. The main battle requires Momohime to attack the monster's horns, evoking the famous Japanese myth of Momotarō. Absent the cultural context, however, this resonance, and the accompanying hint about how to attack the Big Oni, are missing.

This again can easily become frustrating, because the target area on Big Oni is just large enough to be hit occasionally by attacking his body. Because every previous boss in the game is vulnerable at more or less every visible spot, the player might not even think this limitation on Big Oni is possible. Training the player to attack the horns with the randomly encountered oni would have been an ideal solution to this problem. Alternately, Vanillaware could have elected to have only the horns or head flash in response to damage, or to have shown the horns cracking and breaking as the battle progresses. However, the developers, being familiar with the myths about oni, simply might not have thought about how to convey that information to a Western audience. So, another possibility would be for the localization team to slip a hint into the dialogue boxes somewhere.

The journey into hell displays a set of outright mistakes and lost opportunities. Although the difficulty of this section is out of line with the rest of the game, the level of challenge is appropriate to the area being entered. However, because that challenge is not rewarded, what was merely tough becomes frustrating. The strategic requirements for dealing with the oni foes also break with the rest of the game, but it could have been used to prepare the player for a new wrinkle in the upcoming boss. Instead, the demons are dealt with using totally disjoint approaches: raw aggression for the smallest, careful dodging for their larger brethren, and targeted attack for the boss. That makes what could have been Muramasa's most striking and epic section into a frustrating and ultimately tedious slog.

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Capsule: Professor Layton and the Diabolical Box

Final Status: Story finished, most extra puzzles solved.

Put this on your box: A gentleman leaves no puzzle unsolved!

Most intriguing idea: You don't really need to make puzzles part of the story. You can just jam them in there any old way and people will still love it!

Best design decision: Moving the setting around to make each chapter's geography more varied.

Worst design decision: The tea set, a boring game of trial-and-error that doesn't fit the puzzle aesthetic or provide any entertainment.

Summary: Professor Layton and the Diabolical Box follows the same scheme as its predecessor — a mystery presents itself to the Professor, who then must solve puzzles to obtain clues, get around recalcitrant villagers, and just for fun. While some of the puzzles are directly integrated with story events, for the most part they are no more than tangentially related. Diabolical Box has a greater reliance on transfer and picture-scanning puzzles than Mysterious Village, in part because the latter form the basis for almost all the gameplay in the camera minigame. In addition there is a hamster minigame (cursed with appalling voice acting) that also has a puzzle component, in terms of arranging items in the hamster's play area to maximize the number of steps he will take. This pattern is broken with the tea minigame, in which the player must mix components to make particular teas. As mentioned above, the game would have been better without it. The story is little more than an excuse to tramp through environments looking for puzzles, with train-sized plot holes, but it does its job and is charmingly presented. The final twist is unintentionally hilarious, because it suggests that the Professor and Luke kept running into puzzles because they are puzzle maniacs. For the most part, it's more of the same, but when the original is so good, that's not really a problem.

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Chase fixing

Well, the dust has settled at Richmond, and my favorite driver is out of the hunt for the Sprint Cup. Of course, Clint Bowyer was definitively out of the Chase after his poor showing at Atlanta last week. It's been a tough, up and down season for Bowyer, who I like because he's talented, unassuming, and gets no respect, not even from his own employers. They rewarded his great showing the past two years by giving his team and owner points to somebody else (Casey Mears, of all people) and sticking Clint with a brand-new car and crew. The overall implosion of RCR has been a major disappointment this season, but Bowyer's performance, even with the greenest team, has been the best of a mediocre bunch. Still, with Bowyer definitively out of the Chase, and my beloved football starting up again, the question for NASCAR is: what's to keep me watching racing on Sunday afternoon?

Of course, Bowyer isn't the only driver I root for. I've always liked Stewart, and I'm also partial to the international contingent of Montoya and Ambrose (technically, the most Southern of all the drivers). If I'm going to go with the "no respect" theme, then I should also think highly of the Biff, which I do. And of course there are some drivers I root against. I don't like to see anybody wreck, of course, but I might let out a small cackle of glee when the Busch brothers, Hamlin, or "cousin Carl" turn in a poor effort. So I have some interest still in how the Chase plays out. The problem is that due to its structure the Chase is played out long before it ends. As I recall, the Homestead race has only had a real chance to decide the championship once, and the past few Chases have been effectively decided by the time the green flag waved in Phoenix. Most Chasers are eliminated from contention long before that: last year Kyle Busch was through after Dover, and Talladega dramatically thinned the list of possible champions.

The other problem, of course, is that Jimmy Johnson seems to always win this thing. It would be unfair to deliberately calibrate the Chase to specifically stop him, although not without precedent. After all, the Chase was basically invented to prevent Matt Kenseth (or a similarly consistent non-winner) from ever taking home the Cup again. Johnson just does too well on most of the Chase tracks for anyone to catch him. He's not magical, of course, but he's unflappable, and as I've mentioned before, almost fatally unmarketable.

One way to shake things up would be to alter the track selection, especially to thin out the intermediate tracks. Some of those certainly ought to be kept: a Chase without a stop in Texas or Charlotte would be a strange beast, and Kansas always seems to produce an interesting race somehow. New Hampshire's flat oval is just funky enough to stay. Still, there's no good reason to ever race at Fontana, and much less reason to go there in the Chase. If the series is going to hoof it out to Cali, then the Chase should visit Infineon. A road race would diversify the Chase tracks and make it a more complete test of the drivers. I think the racing is actually more entertaining at Watkins Glen (or even rainy Montreal), but the fall weather up north might be too much of an issue. Homestead is also a really uninspiring track, a race nobody would watch if the champion weren't crowned there, and seemingly selected for no better reason than the climate. I think the Chase ought to end at Nascar central in Charlotte, and Homestead's spot given to a more unique and interesting track. Since we're talking about my fantasy here, I'd put a Chase race in Darlington again.

Another way to address the Chase's boring side would be to alter the scoring. This might sound more radical, but the Chase already makes a pretty artificial change to the points. Moreover, the goal of the Chase is not necessarily the same as the season points, so there's no particular reason to keep that scoring system for the Chasers. With that in mind, here are three alternatives.

Option 1: Not enough pie

Chase scoring comes with a simple scale: 10 points for 1st place down to 1 point for 10th place, no points for lower. I would foresee two improvements from this approach. First, because the number of scoring spots is less than the number of racers in the chase, there will be a desperate fight for every position. Second, because the spread of points is so narrow and there's no more penalty for coming in 43rd than 11th, one or two bad races will not completely eliminate a contender. The compressed dynamic range should make it easier for those who are behind to catch up with a few good performances, keeping the Chase drama alive until the checkers wave in Miami. The Chase would be "seeded" by treating regular-season points as a race (so 11th and 12th place Chasers get no points) plus one point per regular-season win. The weakness of this approach is that it gives the non-Chasers a lot of spoiler power, and might de-emphasize Chase wins.

Option 2: "Winning isn't everything, it's the only thing."

Chasers are supposed to be champions. So in the Chase you get 1 point for winning, and 0 points for anything else. Regular-season wins and points, in that order, serve as a tie-breaker and nothing more, except that the regular-season points champion and the winner of the most regular-season races would get one Chase point each. Again, non-Chasers would have a lot of spoiler power, but that would fit in with the organizing scoring principle. More problematic, though, is that the drama could easily be sucked out of this system. In theory the only way to clinch a Championship would be with six wins in this system (maybe less if you started with a bonus), but in practice, and assuming relatively strong competition, three wins might be an insurmountable lead, with other drivers splitting up the other races. So, a strong showing early on could kill the drama.

Option 3: Only racing against each other

Use any points system you want, but in scoring the championship, only consider a driver's position relative to other Chasers. Again, this has the effect of compressing the dynamic range of scoring, meaning that the championship points race will be closer all the way up to the end. It would certainly mitigate the influence of a team being taken out of the championship due to somebody else's wrecks. On the other hand, a team's own errors would also become less damaging, and the whole thing smacks of grading on a curve.

The Chase has done a good job increasing the drama of the last couple of regular-season races and the first few Chase races. The problem continues to be that the system hasn't elevated the season's final few races above their traditional status as irrelevant epilogues to an essentially settled championship run. Shaking up the track selection to emphasize a broader range of skills, and compressing the points range so that the issue remains in doubt all the way to the end, might make the Chase more compelling and interesting to those who, like me (and all those Jr. fans), don't have their favorite driver in the mix.

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We didn't come for the rocks

I wonder if science fiction is really so easy to misunderstand. If sci-fi is just men in tight outfits scrambling across fake plaster rocks until the one in a red shirt gets killed, then of course the whole enterprise is ludicrous. But that's never been the draw. It's not "new stars, new gas giants" that the Enterprise seeks, but "new life, new civilizations". Kids might tune in for the guy in a plastic lizard suit, but adults stayed for the idea of a man without emotions. Could you really live like that? What would it be like? These are the real voyages of the Enterprise in particular and sci-fi in general: not out into space, but inward into the lives of the people out there. Nobody cares that Tatooine is an arid terrestrial with a surface rich in silicon oxides that suffers from persistent dust storms; they care about Luke Skywalker, Han Solo, and what they do in that vast desert. Surely the talented writers at BioWare understand this. Yet, though they set up an intriguing story about people in their sci-fi epic Mass Effect, they inexplicably delivered a game about the rocks.

Mass Effect, in its fiction and its science, clearly belongs to the same genre of space opera as Star Trek and Star Wars. Although the game gives somewhat more consideration to real physics than the other titles, its handling of biology rests at the same level. Most alien species, with the exception of the agreeably freaky hanar, look more or less like us, right down to the mammae, with various kinds of funky head designs to disguise the fact that they have relatably human faces and bodies. This isn't necessarily a bad thing. Although it is true that the medium of videogames frees the developer from the practical limitations that make such "aliens" necessary in live-action, actually implementing a radical design in a believable way (for instance, constructing a set of conversational mannerisms) would be incredibly difficult and would not be guaranteed to yield a creature human players could relate to. Anyway, an exploration of biological possibilities is every bit as much beside the point as the exploration of rocks. What the best sci-fi really explores is ideas about other ways of being — exploring people.

Mass Effect grabs hold of this possibility early on when we are introduced to the Citadel, an enormous space station of mysterious origin that serves as the seat of galactic politics and culture. Here dozens of races butt up against one another, and we are offered glimpses of intriguing new cultures: the libertarian militarism of the turians, the intensely political salarians, the religious hanar, and the slow-speaking elcor who preface every statement with a description of its emotional underpinning. Not all of these races are so interesting (the plight of the quarians quotes far too literally from Battlestar Galactica), but I found the possibilities exciting, especially given the relatively weak position of humanity in this milieu. I thought that the powerful conversation system and the generally well-written characters could be leveraged into an exploration of this rich society. Instead, I was given the 2183 equivalent of an ill-handling dune buggy and sent on the Johnny Shepard Good-Times Tour of the galaxy's most desolate shitholes. Bouncing across the tenth absurdly craggy moonscape to the fifteenth identical base, I wondered why I was still playing.

The answer should be the story, which is a very standard space opera, delivered with just enough cleverness and originality to stay interesting despite its scenery-chewing villains and reliance on played-out fantasy tropes. The player must track down the turncoat galactic agent Saren, who has forged an alliance with the Reapers, an serially-genocidal machine race from the depths of space. He and most of his organic allies have had their minds corrupted by Sovereign, an enormous ship which at first seems to be merely connected to the Reapers. At least in the order I played its missions, the game seemed to time its revelations well and develop them properly.

Yet I came to have three main problems with this tale. The first, a minor point, is that the Conduit spits its passengers out inside the Citadel structure. We are told that a mass relay works by nullifying the mass in a corridor between it and its terminus. The troubling implications of this process for the intervening matter — station, spaceships, and lovely Asari maidens — are not discussed, but I presume the sentient components of that matter would object. The second problem, more concerning, is that the Reapers' behavior is fundamentally inexplicable. The writers eventually give up on explaining their motivation, dismissing the question by telling us that evil metal gods work in mysterious ways.

The final problem, which might be fatal, is that there is no logical reason anything in the story should happen at all. Consider that Mass Effect carefully demonstrates that (1) the Citadel Council trusts Saren completely (Citadel mission), and (2) it is possible to sneak geth soldiers, tanks, and artillery emplacements past the galaxy's most advanced weapons scanners (Noveria mission). Would it not have been considerably easier for Saren to just import a couple thousand geth to the Citadel, walk into the control chamber, and let Sovereign in, relying on the Council's trust for the element of surprise? The only thing that prevents him from doing this is that he showed his hand in the player's first mission on Eden Prime — that is, Saren only needs the Conduit because he was trying to find the Conduit. Hiding the terminus in plain sight on the Citadel was a clever move by the writers, but it ends up being too clever by half, because it only delivers Saren to a place he could have easily reached anyway, were he and Sovereign even half as intelligent as the game wants us to believe.

Nonetheless, the writers managed to hold my interest up until this last, unsatisfying reveal, thanks in large part to solid characters underpinned by excellent voice acting. While some of them have one-note personalities, that single note is played very well, and others show unexpected depth. Codex entries and his own early actions prepared me to see Wrex portrayed as a low-rent Klingon clone, so the elaboration of his backstory as a thoughtful civic leader really worked. Sadly, the ultimate payoff for exploring these stories always seems to be yet another trip to yet another prefab base on yet another hunk of lifeless rock.

The strength of Mass Effect is not its larger plot or barren worlds but its characters and societies. The problem is that although the game's best mechanic is ideally suited to explore that angle, it's left hanging in the wind in favor of a standard power fantasy reliant on wobbly systems. As a shooter the game is merely passable, and the mechanics only get worse from there. The exploration and vehicular combat are irritating, the inventory and party management is trash, and the AI seems only marginally better than that used in DOOM. The hacking / surveying / finding artifacts minigame is a boring, mindless chore. In contrast, the conversation system and the cinematic presentation shine almost every time they appear, making for the most satisfying in-game discussions I've ever seen. Why not take that system and run with it? Why should the most interesting parts of the game be trapped in the completely non-interactive Codex?

I believe BioWare can get this right; they are halfway there already. They have created a universe which, like the best science fiction, is ripe for the exploration of new ideas and new ways of living. Unfortunately, all Mass Effect let us explore was the plaster rocks.

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Proteins stick together when it's crowded

One of the many ways that a living cell does not resemble a test tube is in the degree to which its internal environment is crowded. Cells are crammed full of massive protein complexes, vesicles, organelles, carbohydrates, peptidoglycan, and other assemblies that occupy a great deal of space. The tubes and cuvettes used for biochemical experiments, in contrast, typically contain nothing more than a few proteins and small molecules of interest along with a relatively dilute set of salts and buffering agents. Because many complexes appear to be stabilized by crowding, and excluded volume effects are known to favor compact, folded protein chains, there is considerable interest in estimating how protein behavior changes in the spatially-restricted environment of the cell. In some cases this is approached using NMR to study changes in dynamics and structure inside cells. In a recent issue of Biophysical Journal, groups from Florida State University and Rehovot University, in separate papers, address how crowding affects protein-protein interactions.

Both groups perform biochemical experiments in vitro to examine this question. In order to crowd the solution, they add reagents such as ficoll, polyethylene glycol (PEG), and dextran, and compare the changes in binding and kinetics to solutions that have merely been made more viscous (through the addition of glucose, for instance). Batra et al. study the association of two components of the E. coli DNA polymerase III and find that the presence of crowding agents slightly stabilizes the complex. However, as the size of the crowders is increased, this stabilization is diminished. Batra et al. develop a relatively simple mathematical model that suggests this observation results from the fact that larger particles pack less efficiently, leaving larger "holes" in which the protein complex sees something more like dilute solution.

Phillip et al. study several protein complexes. Similar to Batra's group, they find that crowding with dextran modestly increases the binding affinity of two of their protein pairs, but that this is not replicated for crowding with PEG. Particularly for PEG-1000, there was a clear decrease in affinity, although a non-crowding viscogen (ethylene glycol) had an even greater effect. Phillip et al. also measured the kinetics of binding, and found that the association rates were significantly lower in crowded solutions, as compared to buffer. However, when the rates were corrected for the effect of viscosity, it appeared that the crowding agents slightly increased the association rate. The authors attribute this to excluded volume effects in the binding transition state. The dissociation rate was also slightly reduced in crowded solutions, which the authors explain by the longer lifetime of the encounter complex (allowing a larger fraction of complexes to fall back to the lower-energy bound state).

Given that crowding appears to have a profound effect on the function of certain complexes, the relatively small effects observed in these studies might seem confusing. Batra et al. argue that although each individual binding interaction is only modestly stabilized, the effect should be cumulative. As a result, multi-subunit complexes will experience a greater effect than small heterodimers. Additionally, the most famous examples of crowding enhancement involve very large complexes — the ribosome, decameric assemblies, hemoglobin polymers, etc. In comparison, the complexes formed in these model studies are quite small. It may be that the stabilizing effect of crowding depends to some degree on the size of the complex to be formed. While similar size is difficult to achieve in strictly heterodimeric systems, it should be possible to monitor the assembly of large complexes like GroES/GroEL under crowded conditions. A study of the relationship between the size or number of components in a complex and crowding stabilization may prove instructive.

Batra, J., Xu, K., Qin, S., & Zhou, H. (2009). Effect of Macromolecular Crowding on Protein Binding Stability: Modest Stabilization and Significant Biological Consequences Biophysical Journal, 97 (3), 906-911 DOI: 10.1016/j.bpj.2009.05.032

Phillip, Y., Sherman, E., Haran, G., & Schreiber, G. (2009). Common Crowding Agents Have Only a Small Effect on Protein-Protein Interactions Biophysical Journal, 97 (3), 875-885 DOI: 10.1016/j.bpj.2009.05.026

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