Absolute Free Energies of Biomolecules from Unperturbed Ensembles
Absolute Free Energies of Biomolecules from Unperturbed Ensembles
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DOI：
10.1002/jcc.23448
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发表时间：
2013-12-05
影响因子：
3
通讯作者：
Grigoryan, Gevorg
中科院分区：
文献类型：
--
作者：
Grigoryan, Gevorg
计算大分子结构状态F的绝对自由能是一个具有高度相关性的挑战性问题。本研究提出了一种方法，计算F只使用信息从一个未扰动的模拟的大分子在相关的构象状态，合奏，和环境。由这种方法产生的绝对自由能，被称为局部配置积分与动力学（VALOCIDY）的价值，使替代状态的比较。例如，明确比较氨基酸侧链类似物的溶剂化状态和蒸气状态产生与实验良好一致的溶剂化自由能。此外，模型七肽的替代构象状态（包括未折叠状态）之间的比较产生的自由能差异与分子动力学模拟和实验倾向的数据一致。通过一个稳定β-转角结构的小设计问题，探讨了在计算蛋白质设计中使用VALOCIDY的潜力。当基于VALOCIDY的折叠自由能的估计被用作设计度量时，所得到的序列在设计中使用的原子力场内折叠成所需的结构。基于VALOCIDY的方法还识别天然序列的不同状态，而不管起始模板结构的次要细节，这与传统的固定骨架方法形成鲜明对比。(C)2013 Wiley Periodicals，Inc.
Computing the absolute free energy of a macromolecule's structural state, F, is a challenging problem of high relevance. This study presents a method that computes F using only information from an unperturbed simulation of the macromolecule in the relevant conformational state, ensemble, and environment. Absolute free energies produced by this method, dubbed Valuation of Local Configuration Integral with Dynamics (VALOCIDY), enable comparison of alternative states. For example, comparing explicitly solvated and vaporous states of amino acid sidechain analogs produces solvation free energies in good agreement with experiments. Also, comparisons between alternative conformational states of model heptapeptides (including the unfolded state) produce free energy differences in agreement with data from mu s molecular-dynamics simulations and experimental propensities. The potential of using VALOCIDY in computational protein design is explored via a small design problem of stabilizing a beta-turn structure. When VALOCIDY-based estimation of folding free energy is used as the design metric, the resulting sequence folds into the desired structure within the atomistic force field used in design. The VALOCIDYbased approach also recognizes the distinct status of the native sequence regardless of minor details of the starting template structure, in stark contrast with a traditional fixed-backbone approach. (C) 2013 Wiley Periodicals, Inc.