Tsujishita H, Moriguchi I, Hirono S
New Drug Research Laboratories, Kanebo Ltd., Osaka, Japan.
Biophys J. 1994 Jun;66(6):1815-22. doi: 10.1016/S0006-3495(94)80975-0.
We present here an efficient and accurate procedure for modeling of the three-dimensional structures of polypeptides in the explicit solvent water based on molecular dynamics calculations. Using the toxic domain analog of heat-stable enterotoxin as a model peptide, we examined the utilities of two molecular dynamics techniques with the system containing the explicit solvent. One is the potential-scaled molecular dynamics that had been designed for effective conformational analyses of biomolecules with the explicit solvent water by partially scaling down the potential energies involved in the solute molecules. The other is the variation of Berendsen's weak coupling method (referred to as "hot-solute" method), in which only the solute of the system is heated to a high temperature while the solvent is kept at a normal temperature. Each method successfully increased the rate of folding of the peptides, and the most effective was a combination of the two methods. Moreover, the final structure obtained via cooling process successfully reproduced the experimentally known structure from the extended amino acid sequence using only the distance restraints representing three disulfide bonds in the peptide. Additional distance restraints derived from some of the NOE cross peaks accelerated the folding of the peptide, but gave almost the same structure as in the case without these additional restraints. Because a similar calculation without the explicit solvent could not reproduce the known structure, it is suggested that the explicit solvent water could play an important role in the modeling. The methods presented here have the potential for accurate modeling even when less experimental information was available.
我们在此展示了一种基于分子动力学计算，在显式溶剂水中对多肽三维结构进行建模的高效且准确的方法。以热稳定肠毒素的毒性结构域类似物作为模型肽，我们在包含显式溶剂的体系中检验了两种分子动力学技术的效用。一种是势能缩放分子动力学，它通过部分降低溶质分子所涉及的势能，专为在显式溶剂水中对生物分子进行有效的构象分析而设计。另一种是对贝伦德森弱耦合方法的改进（称为“热溶质”方法），其中仅将体系中的溶质加热到高温，而溶剂保持在常温。每种方法都成功提高了肽的折叠速率，最有效的是两种方法的结合。此外，通过冷却过程获得的最终结构仅使用代表肽中三个二硫键的距离约束，就成功地从延伸的氨基酸序列中重现了实验已知结构。源自一些核Overhauser效应（NOE）交叉峰的额外距离约束加速了肽的折叠，但得到的结构与没有这些额外约束时几乎相同。由于在没有显式溶剂的情况下进行类似计算无法重现已知结构，因此表明显式溶剂水在建模中可能起着重要作用。本文提出的方法即使在可用实验信息较少的情况下，也具有进行准确建模的潜力。
