Department of Chemistry and of Biochemistry, Washington University, St. Louis, Missouri 63105, United States.
J Am Chem Soc. 2012 Sep 26;134(38):15970-8. doi: 10.1021/ja306803v. Epub 2012 Sep 17.
The conformations and stabilities of the β-hairpin model peptides of Waters (Riemen, A. J.; Waters, M. L. Biochemistry 2009, 48, 1525; Hughes, R. M.; Benshoff, M. L.; Waters, M. L. Chemistry 2007, 13, 5753) have been experimentally characterized as a function of lysine ε-methylation. These models were developed to explore molecular recognition of known epigenetic recognition motifs. This system offered an opportunity to computationally examine the role of cation-π interactions, desolvation of the ε-methylated ammonium groups, and aromatic/aromatic interactions on the observed differences in NMR spectra. AMOEBA, a second-generation force field (Ponder, J. W.; Wu, C.; Ren, P.; Pande, V. S.; Chodera, J. D.; Schnieders, M. J.; Haque, I.; Mobley, D. L.; Lambrecht, D. S.; DiStasio, R. A., Jr.; Head-Gordon, M.; Clark, G. N.; Johnson, M. E.; Head-Gordon, T. J. Phys. Chem. B 2010, 114, 2549), was chosen as it includes both multipole electrostatics and polarizability thought to be essential to accurately characterize such interactions. Independent parametrization of ε-methylated amines was required from which aqueous solvation free energies were estimated and shown to agree with literature values. Molecular dynamics simulations (100 ns) using the derived parameters with model peptides, such as Ac-R-W-V-W-V-N-G-Orn-K(Me)(n)-I-L-Q-NH(2), where n = 0, 1, 2, or 3, were conducted in explicit solvent. Distances between the centers of the indole rings of the two-tryptophan residues, 2 and 4, and the ε-methylated ammonium group on Lys-9 as well as the distance between the N- and C-termini were monitored to estimate the strength and orientation of the cation-π and aromatic/aromatic interactions. In agreement with the experimental data, the stability of the β-hairpin increased significantly with lysine ε-methylation. The ability of MD simulations to reproduce the observed NOEs for the four peptides was further estimated for the monopole-based force fields, AMBER, CHARMM, and OPLSAA. AMOEBA correctly predicted over 80% of the observed NOEs for all 4 peptides, while the three-monopole force fields were 40-50% predictive in only 2 cases and approximately 10% in the other 10 examples. Preliminary analysis suggests that the decreased cost of desolvation of the substituted ammonium group significantly compensated for the reduced cation-π interaction resulting from the increased separation due to steric bulk of the ε-methylated amines.
赖门（Riemen，A. J.；沃特斯，M. L.）和沃特斯（Waters，M. L.）的β发夹模型肽的构象和稳定性已作为赖氨酸ε-甲基化的函数进行了实验表征。这些模型是为了探索已知表观遗传识别基序的分子识别而开发的。该系统提供了一个机会，可以计算检查阳离子-π相互作用、ε-甲基化铵基团的去溶剂化以及芳香/芳香相互作用对观察到的 NMR 谱差异的作用。第二代力场（Ponder，J. W.；Wu，C.；Ren，P.；Pande，V. S.；Chodera，J. D.；Schnieders，M. J.；Haque，I.；Mobley，D. L.；Lambrecht，D. S.；DiStasio，R. A.，Jr.；Head-Gordon，M.；Clark，G. N.；Johnson，M. E.；Head-Gordon，T. J. Phys. Chem. B 2010，114，2549）中的 AMOEBA 被选择，因为它包括多极静电和极化率，这些被认为是准确描述此类相互作用所必需的。需要对ε-甲基化胺进行独立参数化，以便估算水溶剂化自由能，并证明其与文献值一致。使用衍生参数在模型肽（例如 Ac-R-W-V-W-V-N-G-Orn-K（Me）（n）-I-L-Q-NH（2），其中 n = 0、1、2 或 3）中进行 100 ns 的分子动力学模拟在明胶溶剂中进行。监测两个色氨酸残基的吲哚环中心之间的距离 2 和 4 以及赖氨酸 9 上的ε-甲基化铵基团与 N 和 C 末端之间的距离，以估计阳离子-π和芳香/芳香相互作用的强度和方向。与实验数据一致，赖氨酸 ε-甲基化显著增加了β发夹的稳定性。进一步使用基于偶极子的力场 AMBER、CHARMM 和 OPLSAA 对 4 种肽的单极子力场模拟重现观察到的 NOE 的能力进行了估计。AMOEBA 正确预测了所有 4 种肽的 80%以上的观察到的 NOE，而三种偶极子力场在仅 2 种情况下的预测率为 40-50%，在其他 10 种情况下约为 10%。初步分析表明，取代的铵基团去溶剂化的成本降低显著弥补了由于 ε-甲基化胺的空间位阻导致的阳离子-π相互作用的降低。
