Selection originating from protein foldability: I. A new method to estimate selection temperature

TL;DR

This paper introduces a new, simplified method to estimate the effective selection temperature of proteins by analyzing mutation-induced interaction changes and their variances, aligning well with experimental data.

Contribution

It presents a novel approach to estimate selection temperature and related thermodynamic parameters from mutation effects using a maximum entropy model and the random energy model.

Findings

Estimated $ ext{Δ}G_{ND}$ values agree with experimental data for 5 proteins.

The method provides reasonable estimates of $T_s$, $T_g$, and $ ext{Δ}G_{ND}$.

Variance of mutation effects is nearly constant across protein families.

Abstract

The probability distribution of sequences with maximum entropy that satisfies a given amino acid composition at each site and a given pairwise amino acid frequency at each site pair is a Boltzmann distribution with $\exp(-\psi_N)$, where the total interaction $\psi_N$ is represented as the sum of one body and pairwise interactions. A protein folding theory based on the random energy model (REM) indicates that the equilibrium ensemble of natural protein sequences is a canonical ensemble characterized by $\exp(-\Delta G_{ND}/k_B T_s)$ or by $\exp(- G_{N}/k_B T_s)$ if an amino acid composition is kept constant, meaning $\psi_N = \Delta G_{ND}/k_B T_s +$ constant, where $\Delta G_{ND} \equiv G_N - G_D$, $G_N$ and $G_D$ are the native and denatured free energies, and $T_s$ is the effective temperature of natural selection. Here, we examine interaction changes ($\Delta \psi_N$) due to single nucleotide nonsynonymous mutations, and have found that the variance of their $\Delta \psi_N$ over all sites hardly depends on the $\psi_N$ of each homologous sequence, indicating that the variance of $\Delta G_N (= k_B T_s \Delta \psi_N)$ is nearly constant irrespective of protein families. As a result, $T_s$ is estimated from the ratio of the variance of $\Delta \psi_N$ to that of a reference protein, which is determined by a direct comparison between $\Delta\Delta \psi_{ND} (\simeq \Delta \psi_N)$ and experimental $\Delta\Delta G_{ND}$. Based on the REM, glass transition temperature $T_g$ and $\Delta G_{ND}$ are estimated from $T_s$ and experimental melting temperatures ($T_m$) for 14 protein domains. The estimates of $\Delta G_{ND}$ agree well with their experimental values for 5 proteins, and those of $T_s$ and $T_g$ are all within a reasonable range. This method is coarse-grained but much simpler in estimating $T_s$, $T_g$ and $\Delta\Delta G_{ND}$ than previous methods.