Experiment showed that the response of a genotype to mutation, i.e., the magnitude of mutational change in a phenotypic property, can be correlated with the extent of phenotypic fluctuation among genetic clones. To address a possible statistical mechanical basis for such phenomena at the protein level, we consider a simple hydrophobic-polar lattice protein-chain model with an exhaustive mapping between sequence (genotype) and conformational (phenotype) spaces. Using squared endto-end distance, RN2, as an example conformational property, we study how the thermal fluctuation of a sequence's RN2 may be predictive of the changes in the Boltzmann average (RN2) caused by single-point mutations on that sequence. We found that sequences with the same ground-state (R N2 exhibit a funnel-like organization under conditions favorable to chain collapse or folding: fluctuation (standard deviation a) of RN2 tends to increase with mutational distance from a prototype sequence whose (RN2) deviates little from its (RN2. In general, large mutational decreases in (RN2) or in a are only possible for some, though not all, sequences with large a values. This finding suggests that single-genotype phenotypic fluctuation is a necessary, though not sufficient, indicator of evolvability toward genotypes with less phenotypic fluctuations. © 2010 by the Biophysical Society.
Chen, T., Vernazobres, D., Yomo, T., Bornberg-Bauer, E., & Chan, H. S. (2010). EvoIvability and single-genotype fluctuation in phenotypic properties: A simple heteropolymer model. Biophysical Journal, 98(11), 2487–2496. https://doi.org/10.1016/j.bpj.2010.02.046