Druart Karen, Bigot Julien, Audit Edouard, Simonson Thomas
Laboratoire de Biochimie (CNRS UMR7654), Ecole Polytechnique , Palaiseau, France.
Maison de la Simulation, CEA, CNRS, Univ. Paris-Sud, UVSQ, Université Paris-Saclay , 91191 Gif-sur-Yvette, France.
J Chem Theory Comput. 2016 Dec 13;12(12):6035-6048. doi: 10.1021/acs.jctc.6b00421. Epub 2016 Nov 4.
Multistate protein design explores side chain mutations, with the backbone allowed to sample a small, predetermined library of conformations. To achieve Boltzmann sampling of sequences and conformations, we use a hybrid Monte Carlo (MC) scheme: a trial hop between backbone models is followed by a short MC segment where side chain rotamers adjust to the new backbone, before applying a Metropolis-like acceptance test. The theoretical form and a practical approximation for the acceptance test are derived. We then compute backbone conformational free energies for two SH2 and SH3 proteins using different routes and protocols, and verify that for simple test problems, the free energy behaves like a state function, a hallmark of Boltzmann sampling.
多状态蛋白质设计探索侧链突变，同时允许主链在一个小的、预先确定的构象库中进行采样。为了实现序列和构象的玻尔兹曼采样，我们使用了一种混合蒙特卡罗（MC）方案：在主链模型之间进行一次试验跳跃，随后是一个短的MC片段，在此期间侧链旋转异构体适应新的主链，然后进行类似 metropolis 的接受测试。推导了接受测试的理论形式和实际近似值。然后，我们使用不同的途径和协议计算了两种 SH2 和 SH3 蛋白的主链构象自由能，并验证了对于简单的测试问题，自由能的行为类似于状态函数，这是玻尔兹曼采样的一个标志。
