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.
Highlights
Side-chains of amino-acid residues encode the information governing a protein’s three-dimensional fold
These proteins are selected under requirements that they have no missing residues; their structural resolutions are better than 1.6 A ; and no pairs have more than 20% sequence identity
Each chosen X-ray structure is very similar to its corresponding NMR structures with small RMSD [25], X-ray structures generally have higher side-chain entropy (SCE) than the corresponding NMR structures. To see how this is related to their packing, we show in Figure 4 the average DSXN of a protein versus DRg 1⁄4 radii of gyration (Rg),X-ray À Rg,NMR, the average difference of the radius of gyration of backbone atoms between X-ray and NMR structures, for all the 23 proteins
Summary
Side-chains of amino-acid residues encode the information governing a protein’s three-dimensional fold. Recent studies have shown that many different self-avoiding side-chain packing (called the side-chain conformation of a backbone structure ) may exist for a given native backbone structure [5,6,7]. It is well-recognized that the so-called ‘‘native protein structure’’ is an ensemble of structures instead of a single structure as normally seen from Xray crystallography [8,9,10,11]. With the aid of a new Monte Carlo method, we can accurately estimate the SCE of proteins based on a realistic model with all heavy atoms explicitly represented
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