Department of Chemistry, Indian Institute of Technology, Guwahati, Assam 781039, India.
J Chem Phys. 2012 Sep 7;137(9):094502. doi: 10.1063/1.4748101.
To understand the mechanism of protein protection by the osmolyte trimethylamine-N-oxide (TMAO) at high pressure, using molecular dynamics (MD) simulations, solvation of hydrophobic group is probed in aqueous solutions of TMAO over a wide range of pressures relevant to protein denaturation. The hydrophobic solute considered in this study is neopentane which is a considerably large molecule. The concentrations of TMAO range from 0 to 4 M and for each TMAO concentration, simulations are performed at five different pressures ranging from 1 atm to 8000 atm. Potentials of mean force are calculated and the relative stability of solvent-separated state over the associated state of hydrophobic solute are estimated. Results suggest that high pressure reduces association of hydrophobic solutes. From computations of site-site radial distribution function followed by analysis of coordination number, it is found that water molecules are tightly packed around the nonpolar particle at high pressure and the hydration number increases with increasing pressure. On the other hand, neopentane interacts preferentially with TMAO over water and although hydration of neopentane reduces in presence of this osmolyte, TMAO does not show any tendency to prevent the pressure-induced dispersion of neopentane moieties. It is also observed that TMAO molecules prefer a side-on orientation near the neopentane surface, allowing its oxygen atom to form favorable hydrogen bonds with water while maintaining some hydrophobic contacts with neopentane. Analysis of hydrogen-bond properties and solvation characteristics of TMAO reveals that TMAO can form hydrogen bonds with water and it reduces the identical nearest neighbor water molecules caused by high hydrostatic pressures. Moreover, TMAO enhances life-time of water-water hydrogen bonds and makes these hydrogen bonds more attractive. Implication of these results for counteracting effect of TMAO against protein denaturation at high pressures are discussed.
为了理解渗透剂三甲胺 N-氧化物（TMAO）在高压下保护蛋白质的机制，我们使用分子动力学（MD）模拟，在与蛋白质变性相关的宽压力范围内探测 TMAO 水溶液中疏水分子的溶剂化作用。在这项研究中，考虑的疏水分子是新戊烷，它是一种相当大的分子。TMAO 的浓度范围为 0 至 4 M，对于每个 TMAO 浓度，在从 1 大气压到 8000 大气压的五个不同压力下进行模拟。计算平均力势，并估计疏水分子溶剂分离状态相对于缔合状态的相对稳定性。结果表明，高压降低了疏水分子的缔合。通过计算位点-位点径向分布函数并分析配位数，发现高压下水分子紧密地围绕非极性粒子排列，并且随着压力的增加，水合数增加。另一方面，新戊烷优先与 TMAO 而不是水相互作用，尽管在这种渗透剂存在下，新戊烷的水合作用减少，但 TMAO 没有表现出任何阻止新戊烷部分在压力下分散的趋势。还观察到 TMAO 分子在新戊烷表面附近优先采用侧位取向，允许其氧原子与水形成有利的氢键，同时与新戊烷保持一些疏水接触。对 TMAO 的氢键性质和溶剂化特性的分析表明，TMAO 可以与水形成氢键，并减少由高静水压力引起的相同最近邻水分子。此外，TMAO 增强了水-水氢键的寿命，并使这些氢键更具吸引力。讨论了这些结果对 TMAO 在高压下对抗蛋白质变性的拮抗作用的影响。
