The role of local versus nonlocal physicochemical restraints in determining protein native structure

Abstract

The tertiary structure of a native protein is dictated by the interplay of local secondary structure propensities, hydrogen bonding, and tertiary interactions. It is argued that the space of known protein topologies covers all single domain folds and results from the compactness of the native structure and excluded volume. Protein compactness combined with the chirality of the protein's side chains also yields native-like Ramachandran plots. It is the many-body, tertiary interactions among residues that collectively select for the global structure that a particular protein sequence adopts. This explains why the recent advances in deep-learning approaches that predict protein side-chain contacts, the distance matrix between residues, and sequence alignments are successful. They succeed because they implicitly learned the many-body interactions among protein residues.