Predicting the tolerance of proteins to random amino acid substitution

¹ Keck Graduate Institute of Applied Life Sciences
² California Institute of Technology

^* To whom correspondence should be addressed. E-mail: wilke{at}caltech.edu.

Submitted on February 28, 2005
Revised on May 9, 2005
Accepted on 16 August 2005

	Abstract

We have recently proposed a thermodynamic model that predicts the tolerance of proteins to random amino acid substitutions. Here we test this model against extensive simulations with compact lattice proteins, and find that the overall performance of the model is very good. We also derive an approximate analytic expression for the fraction of mutant proteins that fold stably to the native structure, P_f(m), as a function of the number of amino acid substitutions m, and present several methods to estimate the asymptotic behavior of P_f(m) for large m. We test the accuracy of all approximations against our simulation results, and find good overall agreement between the approximations and the simulation measurements.

Key Words: lattice proteins, mutagenesis, neutral mutations, neutrality, protein evolution, protein stability

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