  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, finding out that an extended neutral network in sequence space is
associated to 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 against the original
Kimura's 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.
