Baumketner Andrij, Shea Joan-Emma
Department of Chemistry and Biochemistry, University of California at Santa Barbara, Santa Barbara, California 93106, USA.
J Phys Chem B. 2005 Nov 17;109(45):21322-8. doi: 10.1021/jp051325a.
Replica exchange molecular dynamics simulations were performed to investigate the effects of different electrostatic treatments on the structure and thermodynamics of a small beta-hairpin forming peptide. Three different electrostatic schemes were considered: regular cutoffs, generalized reaction field (GRF), and particle mesh Ewald (PME), with the peptide modeled using OPLS/AA all-atom force field with explicit TIP3P water. Both the GRF and PME methods yielded results consistent with experiment, with free energy surfaces displaying a single minimum corresponding to the native beta-hairpin structure. In contrast, use of straight cutoffs led to the population of an additional local minimum corresponding to nonhairpin conformations that compete with the formation of the native beta-hairpin at low temperatures. This extra minimum would not be apparent in conventional constant-temperature molecular dynamics simulations run for a few nanoseconds. This result points to the critical need of careful sampling of conformational space to assess the quality of different numerical treatments of long-range forces. While differences emerged in the nature of the unfolded states populated using PME and GRF approaches, simulations on the beta-hairpin forming peptide and on two additional control peptides indicate that the GRF treatment of electrostatics offers a satisfactory compromise between accuracy and computational speed for the identification of low-energy conformations. A GRF-based approach emerges as a viable means for treating larger biological systems that would be prohibitively costly to simulate using PME methods.
进行了复制交换分子动力学模拟，以研究不同静电处理对一种形成小β-发夹结构肽的结构和热力学的影响。考虑了三种不同的静电方案：常规截断、广义反应场（GRF）和粒子网格埃瓦尔德（PME），肽使用OPLS/AA全原子力场并结合显式TIP3P水进行建模。GRF和PME方法都产生了与实验一致的结果，自由能表面显示出一个对应于天然β-发夹结构的单一最小值。相比之下，使用直接截断会导致出现一个额外的局部最小值，对应于非发夹构象，在低温下与天然β-发夹的形成相互竞争。在传统的持续几纳秒的恒温分子动力学模拟中，这个额外的最小值并不明显。这一结果表明，为了评估不同长程力数值处理的质量，仔细采样构象空间至关重要。虽然使用PME和GRF方法填充的未折叠状态的性质存在差异，但对形成β-发夹的肽和另外两种对照肽的模拟表明，GRF静电处理在识别低能构象的准确性和计算速度之间提供了令人满意的折衷方案。基于GRF的方法成为处理更大生物系统的可行手段，而使用PME方法模拟这些系统的成本过高。
