Academic journal article Genetics

Thermodynamics of Neutral Protein Evolution

Academic journal article Genetics

Thermodynamics of Neutral Protein Evolution

Article excerpt

ABSTRACT

Naturally evolving proteins gradually accumulate mutations while continuing to fold to stable structures. This process of neutral evolution is an important mode of genetic change and forms the basis for the molecular clock. We present a mathematical theory that predicts the number of accumulated mutations, the index of dispersion, and the distribution of stabilities in an evolving protein population from knowledge of the stability effects (ΔΔG values) for single mutations. Our theory quantitatively describes how neutral evolution leads to marginally stable proteins and provides formulas for calculating how fluctuations in stability can overdisperse the molecular clock. It also shows that the structural influences on the rate of sequence evolution observed in earlier simulations can be calculated using just the single-mutation ΔΔG values. We consider both the case when the product of the population size and mutation rate is small and the case when this product is large, and show that in the latter case the proteins evolve excess mutational robustness that is manifested by extra stability and an increase in the rate of sequence evolution. All our theoretical predictions are confirmed by simulations with lattice proteins. Our work provides a mathematical foundation for understanding how protein biophysics shapes the process of evolution.

(ProQuest Information and Learning: ... denotes formulae omitted.)

PROTEINS evolve largely through the slow accumulation of amino acid substitutions. Over evolutionary time, this process of sequence divergence creates homologous proteins that differ at the majority of their residues, yet still fold to similar structures that often perform conserved biochemical functions (LESK and CHOTHIA 1980). The maintenance of structure and function during sequence divergence suggests that much of protein evolution is neutral in the sense that observed sequence changes frequently do not alter a protein's ability to fold and adequately perform the biochemical function necessary to enable its host organism to survive. This comparative evidence for neutrality in protein evolution has been corroborated by experimental studies showing that the mutations separating diverged sequences often have no effect other than modest and additive changes to stability (SERRANO et al. 1993) and that a large fraction of random mutations do not detectably alter a protein's structure or function (SHORTLE and LIN 1985; PAKULA et al. 1986; LOEB et al. 1989; GUO et al. 2004; BLOOM et al. 2005, 2006a). In this respect, it seems that protein evolution should be well described by Kimura's neutral theory of evolution, which holds that most genetic change is due to the stochastic fixation of neutral mutations (KIMURA 1983). One of the key predictions of the neutral theory is that assuming a constant mutation rate, the number of mutations separating two proteins should be proportional to the time since their divergence (KIMURA 1983). Indeed, the observation by ZUCKERKANDL and PAULING (1965) that proteins are "molecular clocks" that accumulate mutations at a roughly constant rate has long been taken as one of the strongest pieces of evidence supporting the neutral theory (OHTA and KIMURA 1971).

However, mutations that are neutral with respect to a protein's capacity to perform its biological function often affect protein thermodynamics. The biological functions of most proteins depend on their ability to fold to thermodynamically stable native structures (ANFINSEN 1973). Yet natural proteins are typically only marginally stable, with free energies of folding (ΔG^sub f^) between -5 and -15 kcal/mol (FERSHT 1999). Most random mutations to proteins are destabilizing (PAKULA et al. 1986; MATTHEWS 1993; GODOY-RUIZ et al. 2004; KUMAR et al. 2006), and their effects on stability (measured as ΔΔG, the ΔG^sub f^ of the mutant protein minus the ΔG^sub f^ of the wild-type protein) are frequently of the same magnitude as a protein's net stability. …

Search by... Author
Show... All Results Primary Sources Peer-reviewed

Oops!

An unknown error has occurred. Please click the button below to reload the page. If the problem persists, please try again in a little while.