Application of torsion angle molecular dynamics for efficient sampling of protein conformations
Application of torsion angle molecular dynamics for efficient sampling of protein conformations
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DOI：
10.1002/jcc.20293
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发表时间：
2005-11-30
影响因子：
3
通讯作者：
Brooks, CL
中科院分区：
文献类型：
--
作者：
Chen, JH;Im, W;Brooks, CL
我们研究扭转角分子动力学（TAMD）的应用，以增加肽和蛋白质的构象采样。蛋白质有趣的构象变化主要涉及扭转自由度。在扭转空间中进行分子动力学不仅明确地采样最相关的自由度，而且还允许更大的积分时间步长，消除键和角自由度。然而，共价几何需要在内部坐标动力学过程中固定，这可能会在广泛参数化的现代笛卡尔蛋白质力场中对潜在的势面引入严重的扭曲。“投影”方法（Katritch等人，J Comput Chem 2003，24，254-265）被扩展以从源笛卡尔力场构建精确的内部坐标力场（ICFF）。扭转交叉项修正构造从本地分子片段，连同软化的货车德瓦尔斯和静电相互作用，用于恢复潜在的表面，并纳入隐含的键和角度的灵活性。二肽模型的MD模拟表明，主链phi/psi和侧链X-1角度的完全灵活性几乎恢复。TAMD在增强构象采样的功效，然后进一步检查小肽的折叠模拟和蛋白质NMR结构的细化实验。结果表明，可以可靠地实现构象采样效率的几倍增加。目前的研究还揭示了一些复杂的内在性质的内部坐标动力学，超越能量守恒，可以限制的最大尺寸的积分时间步长，从而实现的增益采样效率。(c)2005 Wiley Periodicals，Inc.
We investigate the application of torsion angle molecular dynamics (TAMD) to augment conformational sampling of peptides and proteins. Interesting conformational changes in proteins mainly involve torsional degrees of freedom. Carrying out molecular dynamics in torsion space does not only explicitly sample the most relevant degrees of freedom, but also allows larger integration time steps with elimination of the bond and angle degrees of freedom. However, the covalent geometry needs to be fixed during internal coordinate dynamics, which can introduce severe distortions to the underlying potential surface in the extensively parameterized modern Cartesian-based protein force fields. A "projection" approach (Katritch et al. J Comput Chem 2003, 24, 254-265) is extended to construct an accurate internal coordinate force field (ICFF) from a source Cartesian force field. Torsion crossterm corrections constructed from local molecular fragments, together with softened van der Waals and electrostatic interactions, are used to recover the potential surface and incorporate implicit bond and angle flexibility. MD simulations of dipeptide models demonstrate that full flexibility in both the backbone phi/psi and side chain X-1 angles are virtually restored. The efficacy of TAMD in enhancing conformational sampling is then further examined by folding simulations of small peptides and refinement experiments of protein NMR structures. The results show that an increase of several fold in conformational sampling efficiency can be reliably achieved. The current study also reveals some complicated intrinsic properties of internal coordinate dynamics, beyond energy conservation, that can limit the maximum size of the integration time step and thus the achievable gain in sampling efficiency. (c) 2005 Wiley Periodicals, Inc.