Schmitz U, Ulyanov N B, Kumar A, James T L
Department of Pharmaceutical Chemistry, University of California, San Francisco 94143-0446.
J Mol Biol. 1993 Nov 20;234(2):373-89. doi: 10.1006/jmbi.1993.1593.
For conformationally flexible molecules in solution, NMR-derived distance restraints are time-averaged. In contrast to deriving structures from NMR distance constraints via conventional restrained molecular dynamics (rMD), the range of conformational flexibility may be better represented by MD simulations using weighted time-averaged restrains (MD-tar). This approach has been utilized for dynamic structure refinement of the DNA octamer [d(GTATAATG].[d(CATATTAC)] which contains the Pribnow box consensus sequence. An improved set of distance restraints was calculated via complete relaxation matrix analysis utilizing the solution structure of the octamer which was determined previously by rMD as a starting model. MD-tar calculations were performed with the program AMBER4 under various conditions, some including explicit solvent. All trajectories generated via MD-tar exhibited reduced constraint energies and average deviations for the distances compared to standard rMD. Quantitative comparison with experimental data, i.e. two-dimensional NOE intensities and COSY-derived coupling constants yielded a significant improvement for MD-tar simulated structures relative to rMD-derived structures. The conformational envelope of the MD-tar structures is wider than that from rMD and even unrestrained MD. Explicit solvent force-fields tightened the conformational envelope, leading to even better agreement with experimental data. All MD-tar simulations exhibit sugar repuckering for basically all residues, yielding a minor population in the low N-region and one or more S-conformers. For most backbone torsion angles, one or more minor conformers were found, while the major conformations generally coincided with those obtained in standard rMD. Distributions of helical parameters for MD-tar trajectories are rather symmetric but slightly broader than those for rMD. Average values and associated standard deviations are discussed with respect to sequence-dependent variations. All trajectories obtained with an explicit solvent force field exhibited a narrower minor groove compared to in vacuo calculations.
对于溶液中构象灵活的分子，核磁共振（NMR）衍生的距离约束是时间平均的。与通过传统受限分子动力学（rMD）从NMR距离约束推导结构不同，构象灵活性的范围可以通过使用加权时间平均约束的分子动力学模拟（MD-tar）更好地表示。这种方法已用于对包含普里布诺框共有序列的DNA八聚体[d(GTATAATG].[d(CATATTAC)]进行动态结构优化。通过完全弛豫矩阵分析，利用先前由rMD确定的八聚体溶液结构作为起始模型，计算出一组改进的距离约束。在各种条件下，使用AMBER4程序进行MD-tar计算，其中一些条件包括显式溶剂。与标准rMD相比，通过MD-tar生成的所有轨迹的约束能量和距离平均偏差均降低。与实验数据（即二维NOE强度和COSY衍生的耦合常数）的定量比较表明，相对于rMD衍生的结构，MD-tar模拟结构有显著改进。MD-tar结构的构象包络比rMD甚至无约束MD的构象包络更宽。显式溶剂力场收紧了构象包络，从而与实验数据的一致性更好。所有MD-tar模拟基本上对所有残基都显示出糖环重排，在低N区域产生少量群体和一个或多个S-构象体。对于大多数主链扭转角，发现了一个或多个次要构象体，而主要构象通常与标准rMD中获得的构象一致。MD-tar轨迹的螺旋参数分布相当对称，但比rMD的分布略宽。讨论了平均值和相关标准偏差与序列依赖性变化的关系。与真空计算相比，所有使用显式溶剂力场获得的轨迹都显示出较窄的小沟。
