当前位置：
X-MOL 学术
›
J. Chem. Inf. Model.
›
论文详情
Our official English website, www.x-mol.net, welcomes your
feedback! (Note: you will need to create a separate account there.)
Conformational Fluctuations in GTP-Bound K-Ras: A Metadynamics Perspective with Harmonic Linear Discriminant Analysis
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2021-09-27 , DOI: 10.1021/acs.jcim.1c00844 Xiaohui Wang 1
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2021-09-27 , DOI: 10.1021/acs.jcim.1c00844 Xiaohui Wang 1
Affiliation
|
Biomacromolecules often undergo significant conformational rearrangements during function. In proteins, these motions typically consist in nontrivial, concerted rearrangement of multiple flexible regions. Mechanistic, thermodynamics, and kinetic predictions can be obtained via molecular dynamics simulations, provided that the simulation time is at least comparable to the relevant time scale of the process of interest. Because of the substantial computational cost, however, plain MD simulations often have difficulty in obtaining sufficient statistics for converged estimates, requiring the use of more-advanced techniques. Central in many enhanced sampling methods is the definition of a small set of relevant degrees of freedom (collective variables) that are able to describe the transitions between different metastable states of the system. The harmonic linear discriminant analysis (HLDA) has been shown to be useful for constructing low-dimensional collective variables in various complex systems. Here, we apply HLDA to study the free-energy landscape of a monomeric protein around its native state. More precisely, we study the K-Ras protein bound to GTP, focusing on two flexible loops and on the region associated with oncogenic mutations. We perform microsecond-long biased simulations on the wild type and on G12C, G12D, G12 V mutants, describe the resulting free-energy landscapes, and compare our predictions with previous experimental and computational studies. The fast interconversion between open and closed macroscopic states and their similar thermodynamic stabilities are observed. The mutation-induced effects include the alternations of the relative stabilities of different conformational states and the introduction of many microscopic metastable states. Together, our results demonstrate the applicability of the HLDA-based protocol for the conformational sampling of multiple flexible regions in folded proteins.
中文翻译：
GTP-Bound K-Ras 中的构象波动：具有谐波线性判别分析的元动力学视角
生物大分子在功能过程中经常发生显着的构象重排。在蛋白质中，这些运动通常包括多个灵活区域的重要、协调的重排。机械、热力学和动力学预测可以通过分子动力学模拟获得，前提是模拟时间至少与相关过程的相关时间尺度相当。然而，由于大量的计算成本，普通的 MD 模拟通常难以为收敛估计获得足够的统计数据，需要使用更先进的技术。许多增强采样方法的核心是定义一小组相关自由度（集体变量），这些自由度能够描述系统不同亚稳态之间的转变。谐波线性判别分析 (HLDA) 已被证明可用于构建各种复杂系统中的低维集体变量。在这里，我们应用 HLDA 来研究单体蛋白质围绕其天然状态的自由能景观。更准确地说，我们研究了与 GTP 结合的 K-Ras 蛋白，重点是两个灵活的环和与致癌突变相关的区域。我们对野生型和 G12C、G12D、G12 V 突变体进行了微秒长的偏置模拟，描述了由此产生的自由能景观，并将我们的预测与之前的实验和计算研究进行了比较。观察到开放和封闭宏观状态之间的快速相互转换及其类似的热力学稳定性。突变诱导效应包括不同构象状态相对稳定性的改变和许多微观亚稳态的引入。总之，我们的结果证明了基于 HLDA 的协议对折叠蛋白质中多个灵活区域的构象采样的适用性。
更新日期：2021-10-25
中文翻译：
GTP-Bound K-Ras 中的构象波动：具有谐波线性判别分析的元动力学视角
生物大分子在功能过程中经常发生显着的构象重排。在蛋白质中，这些运动通常包括多个灵活区域的重要、协调的重排。机械、热力学和动力学预测可以通过分子动力学模拟获得，前提是模拟时间至少与相关过程的相关时间尺度相当。然而，由于大量的计算成本，普通的 MD 模拟通常难以为收敛估计获得足够的统计数据，需要使用更先进的技术。许多增强采样方法的核心是定义一小组相关自由度（集体变量），这些自由度能够描述系统不同亚稳态之间的转变。谐波线性判别分析 (HLDA) 已被证明可用于构建各种复杂系统中的低维集体变量。在这里，我们应用 HLDA 来研究单体蛋白质围绕其天然状态的自由能景观。更准确地说，我们研究了与 GTP 结合的 K-Ras 蛋白，重点是两个灵活的环和与致癌突变相关的区域。我们对野生型和 G12C、G12D、G12 V 突变体进行了微秒长的偏置模拟，描述了由此产生的自由能景观，并将我们的预测与之前的实验和计算研究进行了比较。观察到开放和封闭宏观状态之间的快速相互转换及其类似的热力学稳定性。突变诱导效应包括不同构象状态相对稳定性的改变和许多微观亚稳态的引入。总之，我们的结果证明了基于 HLDA 的协议对折叠蛋白质中多个灵活区域的构象采样的适用性。
京公网安备 11010802027423号