On Side-Chain Conformational Entropy of Proteins

Abstract

The role of side-chain entropy (SCE) in protein folding has long been speculated about but is still not fully understood. Utilizing a newly developed Monte Carlo method, we conducted a systematic investigation of how the SCE relates to the size of the protein and how it differs among a protein's X-ray, NMR, and decoy structures. We estimated the SCE for a set of 675 nonhomologous proteins, and observed that there is a significant SCE for both exposed and buried residues for all these proteins—the contribution of buried residues approaches ∼40% of the overall SCE. Furthermore, the SCE can be quite different for structures with similar compactness or even similar conformations. As a striking example, we found that proteins' X-ray structures appear to pack more “cleverly” than their NMR or decoy counterparts in the sense of retaining higher SCE while achieving comparable compactness, which suggests that the SCE plays an important role in favouring native protein structures. By including a SCE term in a simple free energy function, we can significantly improve the discrimination of native protein structures from decoys. Side-chains of amino acids determine a protein's three-dimensional structure. The flexible nature of side-chains introduces a significant amount of conformational entropy associated with both protein folding and interactions. Despite many studies, the role that this side-chain entropy (SCE) plays in the process of folding and interactions has not been fully understood. Some basic questions about SCE have not been systematically studied. In this study, Zhang and Liu developed an efficient sequential Monte Carlo strategy to accurately estimate the SCE of proteins of arbitrary lengths with a given potential energy function. Using this novel tool, they studied how the SCE scales with the length of the protein, and how the SCE differs among a protein's X-ray, NMR, and decoy structures. They observed that X-ray structures pack more “smartly” than the corresponding decoy and NMR structures: with the same compactness, X-ray structures tend to have larger SCE. A combination of an SCE term with a contact potential energy significantly improved the discrimination between native and decoy structures. The implication of this study is that the SCE contributes so significantly to protein stability that it should be included explicitly in tasks such as structure prediction, protein design, and NMR structure refinement.