Topham Christopher M, Smith Jeremy C
Molecular Forces Consulting, 40 Rue Boyssonne, Toulouse 31400, France; Computational Molecular Biophysics, IWR der Universität Heidelberg, Im Neuenheimer Feld 368, Heidelberg D-69120, Germany; University of Tennessee/Oak Ridge National Laboratory, Center for Molecular Biophysics, P.O. Box 2008, Oak Ridge, TN 37831-6309, USA; Department of Biochemistry and Cellular and Molecular Biology, University of Tennessee, M407 Walters Life Sciences, 1414 Cumberland Avenue, Knoxville, TN 37996, USA.
Computational Molecular Biophysics, IWR der Universität Heidelberg, Im Neuenheimer Feld 368, Heidelberg D-69120, Germany; University of Tennessee/Oak Ridge National Laboratory, Center for Molecular Biophysics, P.O. Box 2008, Oak Ridge, TN 37831-6309, USA; Department of Biochemistry and Cellular and Molecular Biology, University of Tennessee, M407 Walters Life Sciences, 1414 Cumberland Avenue, Knoxville, TN 37996, USA.
Comput Biol Chem. 2015 Feb;54:33-43. doi: 10.1016/j.compbiolchem.2014.11.007. Epub 2014 Dec 3.
Relative amino acid residue solvent accessibility values allow the quantitative comparison of atomic solvent-accessible surface areas in different residue types and physical environments in proteins and in protein structural alignments. Geometry-optimised tri-peptide structures in extended solvent-exposed reference conformations have been obtained for 43 amino acid residue types at a high level of quantum chemical theory. Significant increases in side-chain solvent accessibility, offset by reductions in main-chain atom solvent exposure, were observed for standard residue types in partially geometry-optimised structures when compared to non-minimised models built from identical sets of proper dihedral angles abstracted from the literature. Optimisation of proper dihedral angles led most notably to marked increases of up to 54% in proline main-chain atom solvent accessibility compared to literature values. Similar effects were observed for fully-optimised tri-peptides in implicit solvent. The relief of internal strain energy was associated with systematic variation in N, C(α) and C(β) atom solvent accessibility across all standard residue types. The results underline the importance of optimisation of 'hard' degrees of freedom (bond lengths and valence bond angles) and improper dihedral angle values from force field or other context-independent reference values, and impact on the use of standardised fixed internal co-ordinate geometry in sampling approaches to the determination of absolute values of protein amino acid residue solvent accessibility. Quantum chemical methods provide a useful and accurate alternative to molecular mechanics methods to perform energy minimisation of peptides containing non-standard (chemically modified) amino acid residues frequently present in experimental protein structure data sets, for which force field parameters may not be available. Reference tri-peptide atomic co-ordinate sets including hydrogen atoms are made freely available.
相对氨基酸残基溶剂可及性值能够对蛋白质以及蛋白质结构比对中不同残基类型和物理环境下的原子溶剂可及表面积进行定量比较。在高水平量子化学理论下，已获得了43种氨基酸残基类型处于伸展的溶剂暴露参考构象中的几何优化三肽结构。与从文献中提取的相同二面角集合构建的未最小化模型相比，在部分几何优化结构中，标准残基类型的侧链溶剂可及性显著增加，同时主链原子的溶剂暴露减少。与文献值相比，合适二面角的优化最显著地导致脯氨酸主链原子溶剂可及性显著增加高达54%。在隐式溶剂中对完全优化的三肽也观察到了类似的效果。内部应变能的释放与所有标准残基类型中N、C(α)和C(β)原子溶剂可及性的系统变化相关。结果强调了从力场或其他与上下文无关的参考值优化“硬”自由度（键长和价键角）以及不合适二面角值的重要性，以及对在确定蛋白质氨基酸残基溶剂可及性绝对值的采样方法中使用标准化固定内部坐标几何的影响。量子化学方法为分子力学方法提供了一种有用且准确的替代方法，用于对实验蛋白质结构数据集中经常出现的含有非标准（化学修饰）氨基酸残基的肽进行能量最小化，对于这些肽可能没有可用的力场参数。包括氢原子的参考三肽原子坐标集可免费获取。
