The energetics of off-rotamer protein side-chain conformations

被引:28
作者
Petrella, RJ
Karplus, M
机构
[1] Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA
[2] Univ Strasbourg, Inst Le Bel, Lab Chim Biophys, F-67000 Strasbourg, France
基金
美国国家卫生研究院;
关键词
protein; side-chain; rotamer; energetics; conformation;
D O I
10.1006/jmbi.2001.4965
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Non-rotameric ("off-rotamer") conformations are commonly observed for the side-chains of protein crystal structures. This study examines whether such conformations are real or artifactual by comparing the energetics of on and off-rotamer side-chain conformations calculated with the CHARMM energy function. Energy-based predictions of side-chain orientation are carried out by rigid-geometry mapping in the presence of the nt for 1709 non-polar side-chains in 24 proteins fixed protein environment for which high-resolution (2.0 Angstrom or better) structures are available. For on-rotamer conformations, 97.6 % are correctly predicted; i.e. they correspond to the absolute minima of their local side-chain energy maps (generally to within 10 degrees or less). By contrast, for the observed off-rotamer side-chain conformations, 63.8% are predicted correctly. This difference is statistically significant (P < 0.001) and suggests that while most of the observed off-rotamer conformations are real, many of the erroneously predicted ones are likely to be artifacts of the X-ray refinements. Probabilities for off-rotamer conformations of the non-polar side-chains are calculated to be 5.0-6.1% by adaptive umbrella-sampled molecular dynamics trajectories of individual amino acid residues in vacuum and in the presence of an average protein or aqueous dielectric environment. These results correspond closely to the 5.7% off-rotamer fraction predicted by the rigid-geometry mapping studies. Since these values are about one-half of the 10.2% off-rotamer fraction observed in the X-ray structures, they support the conclusion that many of the latter are artifacts. In both the rigid-geometry mapping and the molecular dynamics studies, the discrepancies between the predicted and observed fractions of off-rotamer conformations are largest for leucine residues (similar to6% versus 16.6%). The simulations for the isolated amino acid residues indicate that the real off-rotamer frequency of 5-6% is consistent with the internal side-chain and local side-chain-backbone energetics and does not originate from shifts due to the protein. The present results suggest that energy-based rotation maps can be used to find side-chain positional artifacts that appear in crystal structures based on refinements in the 2 Angstrom resolution range. (C) 2001 Academic Press.
引用
收藏
页码:1161 / 1175
页数:15
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