Department of Chemistry and The Center for Biotechnology and Drug Design, Georgia State University, Atlanta, Georgia 30302-4098, United States.
J Chem Theory Comput. 2011 Mar 8;7(3):575-81. doi: 10.1021/ct1005399. Epub 2011 Jan 27.
The cis-trans isomerization of peptide bonds is very slow, occurring in hundreds of seconds. Kinetic studies of such processes using straightforward molecular dynamics are currently not possible. Here, we use Kramers' rate theory in the high friction regime in combination with accelerated molecular dynamics in explicit solvent to successfully retrieve the normal rate of cis to trans switching in the glycyl-prolyl dipeptide. Our approach bypasses the time-reweighting problem of the hyperdynamics scheme, wherein the addition of the bias potential alters the transition state regions and avoids an accurate estimation of kinetics. By performing accelerated molecular dynamics at a few different levels of acceleration, the rate of isomerization is enhanced as much as 10(10) to 10(11) times. Remarkably, the normal rates obtained by simply extrapolating to zero bias are within an order of experimental estimates. This provides validation from a kinetic standpoint of the ω torsional parameters of the AMBER force field that were recently revised by matching to experimentally measured equilibrium properties. We also provide a comparative analysis of the performance of the widely used water models, i.e., TIP3P and SPC/E, in estimating the kinetics of cis-trans isomerization. Furthermore, we show that the dynamic properties of bulk water can be corrected by adjusting the collision frequency in a Langevin thermostat, which then allows for better reproduction of cis-trans isomerization kinetics and a closer agreement of rates between experiments and simulations.
肽键的顺反异构化非常缓慢，需要数百秒才能完成。目前，使用直接的分子动力学对这些过程进行动力学研究是不可能的。在这里，我们在高摩擦区域使用 Kramers 速率理论，并结合显式溶剂中的加速分子动力学，成功地恢复了甘氨酰-脯氨酸二肽中顺式到反式转换的正常速率。我们的方法绕过了超动力学方案中时间重加权的问题，其中偏置势的添加改变了过渡态区域，并避免了对动力学的准确估计。通过在几个不同的加速水平上进行加速分子动力学，可以将异构化的速率提高 10^10 到 10^11 倍。值得注意的是，通过简单地外推到零偏置来获得的正常速率与实验估计值在一个数量级内。这从动力学角度验证了最近通过匹配实验测量的平衡性质来修订的 AMBER 力场的 ω 扭转参数。我们还对广泛使用的水模型（即 TIP3P 和 SPC/E）在估计顺反异构化动力学方面的性能进行了比较分析。此外，我们表明可以通过调整 Langevin 定温器中的碰撞频率来修正体相水的动力学性质，这使得更好地再现顺反异构化动力学成为可能，并使实验和模拟之间的速率更接近。
