Structurally constrained protein evolution: results from a lattice simulation

TL;DR

This study uses lattice simulations to explore how protein sequences evolve neutrally while maintaining stability and fold, revealing complex energy landscapes and the rarity of significant structural changes through point mutations.

Contribution

It introduces a lattice model to analyze neutral protein evolution, highlighting the variability of neutral mutation rates and the separation of different structural networks in sequence space.

Findings

Neutral networks connect sequences with the same fold.

High variability in neutral mutation fractions affects evolution rates.

Structural changes are rare but possible through point mutations.

Abstract

We simulate the evolution of a protein-like sequence subject to point mutations, imposing conservation of the ground state, thermodynamic stability and fast folding. Our model is aimed at describing neutral evolution of natural proteins. We use a cubic lattice model of the protein structure and test the neutrality conditions by extensive Monte Carlo simulations. We observe that sequence space is traversed by neutral networks, i.e. sets of sequences with the same fold connected by point mutations. Typical pairs of sequences on a neutral network are nearly as different as randomly chosen sequences. The fraction of neutral neighbors has strong sequence to sequence variations, which influence the rate of neutral evolution. In this paper we study the thermodynamic stability of different protein sequences. We relate the high variability of the fraction of neutral mutations to the complex energy landscape within a neutral network, arguing that valleys in this landscape are associated to high values of the neutral mutation rate. We find that when a point mutation produces a sequence with a new ground state, this is likely to have a low stability. Thus we tentatively conjecture that neutral networks of different structures are typically well separated in sequence space. This results indicates that changing significantly a protein structure through a biologically acceptable chain of point mutations is a rare, although possible, event.