GNEIMO: Generalized Internal Coordinate Molecular Dynamics Methods

描述（由申请人提供）：分子动力学（MD）模拟是结构生物学中一种强大的计算工具，广泛用于理解蛋白质的构象变化和肽的折叠。然而，使用笛卡尔动力学模型的MD模拟受到总模拟时间尺度的限制，对于大蛋白质而言，总模拟时间尺度为数十纳秒。另一方面，生物过程需要微秒的模拟时间。内坐标分子动力学（ICMD）算法已经发展到能够实现更大的模拟时间步长，并且它们在长时间尺度模拟中显示出巨大的前景。尽管ICMD技术前景看好，但进展甚微，这在很大程度上是由于内部坐标模型的额外数学复杂性。我们提出的ICMD算法，以解决和解决的关键瓶颈问题。我们建议开发，验证广义NEIMO（GNEIMO）ICMD方法，允许冻结的键长，键角和键长和使用ICMD方法更广泛的构象搜索使用模型粗化策略。我们还提出了表征ICMD算法的性能的应用程序，如1）保持天然蛋白质结构，2）一个接近天然的同源结构模型的细化，3）折叠的α螺旋和β发夹肽和4）构象变化的小蛋白质。该项目内的各项研究将共同为有效利用ICMD提供算法和路线图。我们将奠定基础，这些算法与广泛使用的MD软件包NAMD更广泛的传播集成。

DESCRIPTION (provided by applicant): Molecular dynamics (MD) simulations is a powerful computational tool in structural biology, widely used for understanding conformational changes in proteins, and folding of peptides. However MD simulations using Cartesian dynamics model is limited by the total simulation time scale being in tens of nanoseconds for large proteins. Biological processes on the other hand need microseconds of simulation time. Internal Coordinate Molecular Dynamics (ICMD) algorithms have been developed to enable larger simulation time-steps and they show great promise in long time scale simulations. Despite their promise, ICMD techniques have made little progress due in large part to the additional mathematical complexity of internal coordinate models. We propose to address and solve the key bottleneck problems with ICMD algorithms. We propose to develop, validate Generalized NEIMO (GNEIMO) ICMD methods that allow freezing of only bond lengths, bond angle and bond lengths and use of ICMD methods for wider conformational search using model coarsening strategies. We also propose to characterize the performance of ICMD algorithms for the applications such as 1) maintaining the native protein structure, 2) refinement of a near native homology structural models, 3) folding of alpha helical and beta hairpin peptides and 4) conformations changes in small proteins. Together, the various studies within this project will provide algorithms and a roadmap for the effective use of ICMD. We will lay the basis for integration of these algorithms with the widely used MD software package NAMD for wider dissemination.