COMPUTATIONAL STUDIES OF COMPLEX PROCESSES IN BIOLOGICAL MACROMOLECULAR SYSTEMS

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 自由能取样模拟渗透通道激酶膜溶剂化溶剂化摘要：本提案是前NRAC拨款资助项目的延续。这些项目利用了分子动力学（MD）模拟多年来在力场精度、长程静电处理、积分算法效率、并行处理和其他技术问题方面的进展。基于详细原子模型的计算可以为理解生物分子系统做出重大贡献。然而，必须制定特殊的策略，以获得可以与实验进行比较的定量有意义的结果。许多问题不能用简单的“蛮力”MD模拟方法来解决。例如，自由能扰动和平均力（PMF）的计算与偏置采样方法沿着多维反应坐标的潜力是一个有吸引力的方法，以克服采样困难，而不牺牲精度。将特殊策略应用于大分子的大尺度运动仍然是非常具有挑战性的。在目前的建议中，我们描述了几个计算项目，旨在了解复杂和多样的生物系统，如：钾通道，酪氨酸激酶的Src家族，谷氨酸受体，并开发和完善一个完全极化力场的生物分子模拟使用经典的德鲁德振荡器模型。如果不能获得超级计算机资源，这些项目就不可能取得有意义的进展。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. free energy sampling simulation permeation channels kinases membranes solvation solvation Abstract: This proposal is the continuation of the projects supported by previous NRAC allocation grants. The projects exploit the advances in molecular dynamics (MD) simulations years with respect to accuracy of force fields, treatment of long-range electrostatics, efficiency of integration algorithms, parallel processing, and other technical issues. Computations based on detailed atomic models can make significant contributions to the understanding of biomolecular systems. It is, however, essential to develop special strategies to get quantitatively meaningful results that can be compared with experiments. Many questions cannot be addressed with simple ``brute force'' MD simulation methods. For example, free energy perturbation and potential of mean force (PMF) calculations with biased sampling methods along multi-dimensional reaction coordinates are an attractive method to overcome the sampling difficulties without sacrificing accuracy. The application of special strategies to large-scale motions in macromolecules remains very challenging. In the current proposal, we describe several computational projects aimed at understanding complex and diverse biological systems such as: potassium channels, tyrosine kinases of the Src family, glutamate receptor, and the development and refinement of a fully polarizable force field for biomolecular simulations using the classical Drude oscillator model. It would not be possible to make meaningful progress in these projects without access to supercomputer resources.