COMPUTATIONAL STUDIES OF COMPLEX PROCESSES IN BIOLOGICAL MACROMOLECULAR SYSTEMS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 自由能采样模拟渗透通道激活膜溶剂化摘要：这项建议是先前NRAC拨款支持的项目的继续。这些项目利用了分子动力学(MD)模拟多年在力场精度、远程静电处理、积分算法的效率、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，开发特殊的策略以获得可以与实验相比较的有数量意义的结果是至关重要的。许多问题不能用简单的“蛮力”MD模拟方法解决。例如，在多维反应坐标上采用有偏采样方法的自由能微扰和平均力势(PMF)计算是一种在不牺牲精度的情况下克服采样困难的有吸引力的方法。将特殊策略应用于大分子的大规模运动仍然非常具有挑战性。在当前的提案中，我们描述了几个旨在了解复杂和多样化的生物系统的计算项目，例如：钾通道、Src家族的酪氨酸激酶、谷氨酸受体，以及利用经典的Drude振子模型开发和改进用于生物分子模拟的完全可极化的力场。如果没有超级计算机资源，就不可能在这些项目中取得有意义的进展。

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.