GNEIMO: Generalized Internal Coordinate Molecular Dynamics Methods

描述（申请人提供）：分子动力学（MD）模拟是结构生物学中强大的计算工具，广泛用于理解蛋白质的构象变化和肽的折叠。然而，基于笛卡尔动力学模型的分子动力学模拟受限于对大分子蛋白质的模拟总时间尺度在几十纳秒以内。另一方面，生物过程需要微秒级的模拟时间。内坐标分子动力学（ICMD）算法已经发展到可以实现更大的模拟时间步长，它们在长时间尺度的模拟中显示出很大的希望。尽管ICMD技术很有前景，但由于内部坐标模型的额外数学复杂性，ICMD技术几乎没有取得进展。我们建议用ICMD算法来解决关键的瓶颈问题。我们建议开发和验证广义NEIMO (GNEIMO) ICMD方法，该方法只允许冻结键长、键角和键长，并使用ICMD方法使用模型粗化策略进行更广泛的构象搜索。我们还提出表征ICMD算法在以下应用中的性能：1)维持天然蛋白质结构，2)改进接近天然同源结构模型，3)α螺旋肽和β发夹肽的折叠，以及4)小蛋白质构象的变化。该项目的各项研究将共同为有效使用ICMD提供算法和路线图。我们将为这些算法与广泛使用的MD软件包NAMD集成奠定基础，以便更广泛地传播。

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.