Why are proteins marginally stable?

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Abstract
Most globular proteins are marginally stable regardless of size or activity. The most common interpretation is that proteins must be marginally stable in order to function, and so marginal stability represents the results of positive selection. We consider the issue of marginal stability directly using model proteins and the dynamical aspects of protein evolution in populations. We find that the marginal stability of proteins is an inherent property of proteins due to the high dimensionality of the sequence space, without regard to protein function. In this way, marginal stability can result from neutral, non‐adaptive evolution. By allowing evolving protein sub‐populations with different stability requirements for functionality to complete, we find that marginally stable populations of proteins tend to dominate. Our results show that functionalities consistent with marginal stability have a strong evolutionary advantage, and might arise because of the natural tendency of proteins towards marginal stability. Proteins 2002;46:105–109.