Laboratory of Computational Biology, National Heart, Lung, and Blood Institute, National Institutes of Health, Rockville, Maryland 20892, United States.
Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, 20 Penn Street, Baltimore, Maryland 21201, United States.
J Phys Chem B. 2021 Oct 28;125(42):11687-11696. doi: 10.1021/acs.jpcb.1c07202. Epub 2021 Oct 15.
Potential energy parameters for α-methyl amino acids were generated with ab initio calculations on α-methyl--acetylalanyl-'-methylamide (the α-methyl "alanine dipeptide") which served as an input to a grid-based correction to the backbone torsional potential (known as CMAP) consistent with the CHARMM36m additive protein force field. The new parameters were validated by comparison with experimentally determined helicities of the 22 residue C-terminal peptide (H10) from apolipoprotein A1 and five α-methylated variants in water and 0.3:0.7 trifluoroethanol (TFE)/water. Conventional molecular dynamics simulation totaling 30 μs for each peptide is in overall good agreement with the experiment, including the increased helicity in 30% TFE. An additional 500 ns of simulation using two-dimensional dihedral biasing (bpCMAP) replica exchange reduced left-handed conformations, increased right-handed helices, and thereby mostly decreased agreement with the experiment. Analysis of side chain-side chain salt bridges suggests that the overestimation of the helical content may be, in part, due to such interactions. The increased helicity of the peptides in 30% TFE arises from decreased hydrogen bonding of the backbone atoms to water and a concomitant increase in intramolecular backbone hydrogen bonds.
使用从头算方法对α-甲基乙酰丙氨酰-'-甲基酰胺（α-甲基“丙氨酸二肽”）进行了计算，生成了α-甲基氨基酸的位能参数，该方法作为一种基于网格的对骨干扭转位能（称为 CMAP）的修正输入，与 CHARMM36m 加性蛋白质力场一致。通过与载脂蛋白 A1 的 22 残基 C 末端肽（H10）和水中的五种α-甲基化变体的实验测定的螺旋性进行比较，验证了新参数。对于每种肽，总计 30 μs 的常规分子动力学模拟与实验总体上非常吻合，包括在 30% TFE 中增加的螺旋性。使用二维二面角偏置（bpCMAP）复制交换进行另外 500 ns 的模拟，减少了左手构象，增加了右手螺旋，从而在很大程度上降低了与实验的一致性。对侧链-侧链盐桥的分析表明，螺旋含量的高估可能部分归因于这种相互作用。肽在 30% TFE 中的螺旋性增加是由于骨干原子与水的氢键减少，以及分子内骨干氢键的增加。
