Unraveling the Coupling between Conformational Changes and Ligand Binding in Ribose Binding Protein Using Multiscale Molecular Dynamics and Free-Energy Calculations
Unraveling the Coupling between Conformational Changes and Ligand Binding in Ribose Binding Protein Using Multiscale Molecular Dynamics and Free-Energy Calculations
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利用多尺度分子动力学和自由能计算揭示核糖结合蛋白构象变化与配体结合之间的耦合
DOI：
10.1021/acs.jpcb.0c11600
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Sugita Yuji
中科院分区：
文献类型：
--
作者：
Ren Weitong;Dokainish Hisham M.;Shinobu Ai;Oshima Hiraku;Sugita Yuji
蛋白质与配体结合后的构象变化通常用几种机制来解释，包括诱导拟合、构象选择或它们的混合。传统的基于原子模型的分子动力学（cMD）模拟方法由于时间尺度的限制，难以模拟蛋白质从开到闭的构象转变。在我们以前的研究中，我们已经开发了一种增强的采样方案（广义副本交换与溶质回火选定的表面带电残基：gREST_SSCR）的多结构域蛋白质，并将其应用于配体介导的构象变化的G134R突变体的核糖结合蛋白（RBPG134R）在溶液中。RBPG 134 R的自由能谱（FEL）包括开放态和闭合态以及两种中间态，开放样和闭合样形式。自由电子激光中只有开放和类开放的形式存在，没有核糖。在目前的研究中，构象变化和配体结合之间的耦合进一步研究使用粗粒分子动力学，多原子cMD，和自由能计算。在cMD模拟中，从开放和开放样形式开始，核糖容易从野生型RBP和RBPG 134 R的结合位点解离。相反，它是稳定的结合位点的模拟从封闭和封闭的形式。自由能计算提供了不同结构的结合亲和力，支持cMD模拟的结果。重要的是，cMD模拟从封闭的结构揭示了过渡到封闭的存在下，绑定核糖。在计算结果的基础上，我们提出了一个分子机制，其中构象选择和诱导拟合分别发生在RBP的开放到闭合转变的前半部分和后半部分。
Conformational changes of proteins upon ligand binding are usually explained in terms of several mechanisms including the induced fit, conformational selection, or their mixtures. Due to the slow time scales, conventional molecular dynamics (cMD) simulations based on the atomistic models cannot easily simulate the open-to-closed conformational transition in proteins. In our previous study, we have developed an enhanced sampling scheme (generalized replica exchange with solute tempering selected surface charged residues: gREST_SSCR) for multidomain proteins and applied it to ligand-mediated conformational changes in the G134R mutant of ribose-binding protein (RBPG134R) in solution. The free-energy landscape (FEL) of RBPG134Rin the presence of a ribose at the binding site included the open and closed states and two intermediates, open-like and closed-like forms. Only the open and open-like forms existed in the FEL without a ribose. In the current study, the coupling between the conformational changes and ligand binding is further investigated using coarse-grained MD, multiple atomistic cMD, and free-energy calculations. The ribose is easily dissociated from the binding site of wild-type RBP and RBPG134Rin the cMD simulations starting from the open and open-like forms. In contrast, it is stable at the binding site in the simulations from the closed and closed-like forms. The free-energy calculations provide the binding affinities of different structures, supporting the results of cMD simulations. Importantly, cMD simulations from the closed-like structures reveal transitions toward the closed one in the presence of a bound ribose. On the basis of the computational results, we propose a molecular mechanism in which conformational selection and induced fit happen in the first and second halves of the open-to-closed transition in RBP, respectively.
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影响因子：
4.4
作者：
Kamiya, Motoshi;Sugita, Yuji
通讯作者：
Sugita, Yuji
使用多状态 Bennett 接受率构建宏观混合双流域 Gō 模型
影响因子：
1.5
作者：
Ai Shinobu;C. Kobayashi;Y. Matsunaga;Y. Sugita
通讯作者：
Y. Sugita
DOI：
10.1021/jp807701h
发表时间：
2009-02-26
期刊：
The journal of physical chemistry. B
影响因子：
--
作者：
Deng Y;Roux B
通讯作者：
Roux B
影响因子：
5.6
作者：
Karanicolas, J;Brooks, CL
通讯作者：
Brooks, CL
影响因子：
3.3
作者：
Wang, Lingle;Friesner, Richard A.;Berne, B. J.
通讯作者：
Berne, B. J.