posted 13. March 2003 03:51                   

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Regarding the idea that NS is just the tool for keeping folks on the bridges. Yes, again I agree, but it becomes a question of kinetics. IOW, how thin and how long is the bridge? One could argue there is a bridge between lead and gold, or between a protein native conformation and a certain misfold. But you never or rarely see them convert because the time constant is billions of years or more. I don't intend these as perfect analogies.

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My point is simply that the existence of a bridge does not alone solve all problems. I would argue that fish did not evolve into amphibia, for example, but I'm not sure there is *no* viable bridge of closely-spaced intermediates between them.

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I don't know what to make of this, we were talking about proteins. Fish-amphibian intermediates are not some mere faintly imaginable possibility, though. You are aware of Ichthyostega I presume...



Fish or amphibian?

posted 22. March 2003 16:47                   

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Protein structures are much more conserved than sequences during evolution. Based on this observation, we investigate the consequences of structural conservation on protein evolution. We study seven of the most studied protein folds, determining that an extended neutral network in sequence space is associated with each of them. Within our model, neutral evolution leads to a non-Poissonian substitution process, due to the broad distribution of connectivities in neutral networks. The observation that the substitution process has non-Poissonian statistics has been used to argue against the original Kimura neutral theory, while our model shows that this is a generic property of neutral evolution with structural conservation. Our model also predicts that the substitution rate can strongly fluctuate from one branch to another of the evolutionary tree. The average sequence similarity within a neutral network is close to the threshold of randomness, as observed for families of sequences sharing the same fold. Nevertheless, some positions are more difficult to mutate than others. We compare such structurally conserved positions to positions conserved in protein evolution, suggesting that our model can be a valuable tool to distinguish structural from functional conservation in databases of protein families. These results indicate that a synergy between database analysis and structurally based computational studies can increase our understanding of protein evolution.

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posted 22. March 2003 17:16                   

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Neutral evolution is the simplest model of molecular evolution and thus it is most amenable to a comprehensive theoretical investigation. In this paper, we characterize the statistical properties of neutral evolution of proteins under the requirement that the native state remains thermodynamically stable, and compare them to the ones of Kimura's model of neutral evolution. Our study is based on the Structurally Constrained Neutral (SCN) model which we recently proposed. We show that, in the SCN model, the substitution rate decreases as longer time intervals are considered, and fluctuates strongly from one branch of the evolutionary tree to another, leading to a non-Poissonian statistics for the substitution process. Such strong fluctuations are also due to the fact that neutral substitution rates for individual residues are strongly correlated for most residue pairs. Interestingly, structurally conserved residues, characterized by a much below average substitution rate, are also much less correlated to other residues and evolve in a much more regular way. Our results could improve methods aimed at distinguishing between neutral and adaptive substitutions as well as methods for computing the expected number of substitutions occurred since the divergence of two protein sequences.

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