Laboratoire de Biologie Structurale de la Cellule (CNRS UMR7654), Ecole Polytechnique, 91128 Palaiseau, France.
Department of Physics, University of Cyprus, PO20537, CY1678 Nicosia, Cyprus.
J Phys Chem A. 2020 Dec 24;124(51):10637-10648. doi: 10.1021/acs.jpca.0c07605. Epub 2020 Nov 10.
We describe methods for physics-based protein design and some recent applications from our work. We present the physical interpretation of a MC simulation in sequence space and show that sequences and conformations form a well-defined statistical ensemble, explored with Monte Carlo and Boltzmann sampling. The folded state energy combines molecular mechanics for solutes with continuum electrostatics for solvent. We usually assume one or a few fixed protein backbone structures and discrete side chain rotamers. Methods based on molecular dynamics, which introduce additional backbone and side chain flexibility, are under development. The redesign of a PDZ domain and an aminoacyl-tRNA synthetase enzyme were successful. We describe a versatile, adaptive, Wang-Landau MC method that can be used to design for substrate affinity, catalytic rate, catalytic efficiency, or the specificity of these properties. The methods are transferable to all biomolecules, can be systematically improved, and give physical insights.
我们描述了基于物理的蛋白质设计方法及其在我们工作中的一些最新应用。我们提出了在序列空间中进行 MC 模拟的物理解释，并展示了序列和构象形成了一个明确的统计系综，通过蒙特卡罗和玻尔兹曼采样进行探索。折叠状态能量结合了溶质的分子力学和溶剂的连续静电学。我们通常假设一个或几个固定的蛋白质骨架结构和离散的侧链旋转异构体。基于分子动力学的方法，引入了额外的骨架和侧链灵活性，正在开发中。PDZ 结构域和氨酰-tRNA 合成酶的重新设计取得了成功。我们描述了一种通用、自适应的 Wang-Landau MC 方法，可用于设计底物亲和力、催化速率、催化效率或这些性质的特异性。这些方法可转移到所有生物分子，可以系统地改进，并提供物理见解。
