Drozdov Alexander N, Grossfield Alan, Pappu Rohit V
Department of Biomedical Engineering, Washington University in St. Louis, Campus Box 1097, St. Louis, Missouri 63130, USA.
J Am Chem Soc. 2004 Mar 3;126(8):2574-81. doi: 10.1021/ja039051x.
Evidence from a variety of spectroscopic probes indicates that (phi, psi) values corresponding to the left-handed polyproline II helix (P(II)) are preferred for short alanine-based peptides in water. On the basis of results from theoretical studies, it is believed that the observed preference is dictated by favorable peptide-solvent interactions, which are realized through formation of optimal hydrogen-bonding water bridges between peptide donor and acceptor groups. In the present study, we address this issue explicitly by analyzing the hydration structure and thermodynamics of 16 low-energy conformers of the alanine dipeptide (N-acetylalanine-N'-methylamide) in liquid water. Monte Carlo simulations in the canonical ensemble were performed under ambient conditions with all-atom OPLS parameters for the alanine dipeptide and the TIP5P model for water. We find that the number of hydrogen-bonded water molecules connecting the peptide group donor and acceptor atoms has no effect on the solvation thermodynamics. Instead, the latter are determined by the work done to fully hydrate the peptide. This work is minimal for conformations that are characterized by a minimal overlap of the primary hydration shells around the peptide donor and acceptor atoms. As a result, peptide-solvent interactions favor "compact" conformations that do not include P(II)-like geometries. Our main conclusion is that the experimentally observed preference for P(II) does not arise due to favorable direct interactions between the peptide and water molecules. Instead, the latter act to unmask underlying conformational preferences that are a consequence of minimizing intrapeptide steric conflicts.
来自各种光谱探针的证据表明，对于水中基于丙氨酸的短肽而言，对应于左手多聚脯氨酸II螺旋（P(II)）的(φ, ψ)值是更可取的。基于理论研究结果，人们认为观察到的这种偏好是由有利的肽-溶剂相互作用所决定的，这种相互作用是通过在肽供体和受体基团之间形成最佳氢键水桥来实现的。在本研究中，我们通过分析丙氨酸二肽（N-乙酰丙氨酸-N'-甲基酰胺）在液态水中的16种低能构象的水合结构和热力学，明确地解决了这个问题。在环境条件下，使用丙氨酸二肽的全原子OPLS参数和水的TIP5P模型，在正则系综中进行了蒙特卡罗模拟。我们发现，连接肽基团供体和受体原子的氢键水分子数量对溶剂化热力学没有影响。相反，后者是由使肽完全水合所做的功决定的。对于那些肽供体和受体原子周围的主要水合壳层重叠最小的构象，这项功是最小的。因此，肽-溶剂相互作用有利于不包括类P(II)几何结构的“紧凑”构象。我们的主要结论是，实验观察到的对P(II)的偏好并非由于肽与水分子之间有利的直接相互作用而产生。相反，后者的作用是揭示潜在的构象偏好，这些偏好是使肽内空间冲突最小化的结果。
