Department of Chemical Engineering , Massachusetts Institute of Technology , Cambridge , Massachusetts 02139 , United States.
Department of Chemistry , Massachusetts Institute of Technology , Cambridge , Massachusetts 02139 , United States.
J Chem Inf Model. 2019 May 28;59(5):2199-2211. doi: 10.1021/acs.jcim.9b00144. Epub 2019 Mar 27.
We investigate unexpectedly short non-covalent distances (<85% of the sum of van der Waals radii) in X-ray crystal structures of proteins. We curate over 11 000 high-quality protein crystal structures and an ultra-high-resolution (1.2 Å or better) subset containing >900 structures. Although our non-covalent distance criterion excludes standard hydrogen bonds known to be essential in protein stability, we observe over 75 000 close contacts (CCs) in the curated protein structures. Analysis of the frequency of amino acids participating in these interactions demonstrates some expected trends (i.e., enrichment of charged Lys, Arg, Asp, and Glu) but also reveals unexpected enhancement of Tyr in such interactions. Nearly all amino acids are observed to form at least one CC with all other amino acids, and most interactions are preserved in the much smaller ultra-high-resolution subset. We quantum-mechanically characterize the interaction energetics of a subset of >5000 CCs with symmetry-adapted perturbation theory to enable decomposition of interactions. We observe the majority of CCs to be favorable. The shortest favorable non-covalent distances are under 2.2 Å and are very repulsive when characterized with classical force fields. This analysis reveals stabilization by a combination of electrostatic and charge-transfer effects between hydrophobic (i.e., Val, Ile, Leu) amino acids and charged Asp or Glu. We also observe a unique hydrogen-bonding configuration between Tyr and Asn/Gln involving both residues acting simultaneously as hydrogen bond donors and acceptors. This work confirms the importance of first-principles simulation in explaining unexpected geometries in protein crystal structures.
我们研究了蛋白质 X 射线晶体结构中出人意料的短非共价距离（<85%范德华半径之和）。我们整理了超过 11000 个高质量蛋白质晶体结构，以及一个超高分辨率（1.2Å 或更好）子集，其中包含>900 个结构。尽管我们的非共价距离标准排除了已知对蛋白质稳定性至关重要的标准氢键，但我们在整理后的蛋白质结构中观察到超过 75000 个紧密接触（CC）。对参与这些相互作用的氨基酸频率的分析表明了一些预期的趋势（即带电荷的 Lys、Arg、Asp 和 Glu 的富集），但也揭示了 Tyr 在这些相互作用中的意外增强。几乎所有的氨基酸都被观察到与所有其他氨基酸形成至少一个 CC，并且大多数相互作用在更小的超高分辨率子集中得以保留。我们使用对称性自适应微扰理论对>5000 个 CC 的子集进行了量子力学特征分析，以实现相互作用的分解。我们观察到大多数 CC 都是有利的。最短的有利非共价距离小于 2.2Å，用经典力场进行特征化时非常排斥。这种分析揭示了静电和电荷转移效应与疏水性（即 Val、Ile、Leu）氨基酸和带电荷的 Asp 或 Glu 之间的相互作用的稳定性。我们还观察到 Tyr 与 Asn/Gln 之间独特的氢键构型，涉及两个残基同时作为氢键供体和受体。这项工作证实了第一性原理模拟在解释蛋白质晶体结构中出人意料的几何形状方面的重要性。
