Are Protein Folds Atypical?

TL;DR

This paper introduces a theoretical framework for understanding protein fold selection based on hydrophobic interactions, showing that common protein folds are the most atypical and thermodynamically stable in a high-dimensional structure space.

Contribution

It provides a novel formulation of the protein folding problem using a high-dimensional space and demonstrates the significance of the designability principle in protein structure selection.

Findings

Atypical structures are more thermodynamically stable.

Common protein folds are the most atypical in the structure space.

A new high-dimensional model links structure and sequence space.

Abstract

Protein structures are a very special class among all possible structures. It was suggested that a ``designability principle'' plays a crucial role in nature's selection of protein sequences and structures. Here we provide a theoretical base for such a selection principle, using a novel formulation of the protein folding problem based on hydrophobic interactions. A structure is reduced to a string of 0's and 1's which represent the surface and core sites, respectively, as the backbone is traced. Each structure is therefore associated with one point in a high dimensional space. Sequences are represented by strings of their hydrophobicities and thus can be mapped into the same space. A sequence which lies closer to a particular structure in this space than to any other structures will have that structure as its ground state. Atypical structures, namely those far away from other structures in the high dimensional space, have more sequences which fold into them, and are thermodynamically more stable. We argue that the most common folds of proteins are the most atypical in the space of possible structures.