Analysis of the Dynamics of a Complex, Multipathway Reaction: Insulin Dimer Dissociation.

IF 2.8 2区 化学 Q3 CHEMISTRY, PHYSICAL
The Journal of Physical Chemistry B Pub Date : 2024-12-26 Epub Date: 2024-12-13 DOI:10.1021/acs.jpcb.4c06933
Kwanghoon Jeong, Spencer C Guo, Sammy Allaw, Aaron R Dinner
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引用次数: 0

Abstract

The protein hormone insulin forms a homodimer that must dissociate to bind to its receptor. Understanding the kinetics and mechanism of dissociation is essential for the rational design of therapeutic analogs. In addition to its physiological importance, this dissociation process serves as a paradigm for coupled (un)folding and (un)binding. Based on previous free energy simulations, insulin dissociation is thought to involve multiple pathways with comparable free energy barriers. Here, we analyze the mechanism of insulin dimer dissociation using a recently developed computational framework for estimating kinetic statistics from short-trajectory data. These statistics indicate that the likelihood of dissociation (the committor) closely tracks the decrease in the number of (native and nonnative) intermonomer contacts and the increase in the number of water contacts at the dimer interface; the transition state with equal likelihood of association and dissociation corresponds to an encounter complex with relatively few native contacts and many nonnative contacts. We identify four pathways out of the dimer state and quantify their contributions to the rate as well as their exchange by computing reactive fluxes. We show that both the pathways and their extents of exchange can be understood in terms of rotations around three axes of the dimer structure. Our results provide insights into the kinetics of insulin analogs and, more generally, how to characterize complex, multipathway processes.

复杂多途径反应的动力学分析:胰岛素二聚体解离。
蛋白质激素胰岛素形成一种同型二聚体,必须解离才能与其受体结合。了解解离的动力学和机制对于合理设计治疗类似物至关重要。除了生理上的重要性外,这种解离过程还可以作为耦合(非)折叠和(非)结合的范例。基于先前的自由能模拟,胰岛素解离被认为涉及多种具有可比自由能障碍的途径。在这里,我们分析胰岛素二聚体解离的机制使用最近开发的计算框架估计动力学统计从短轨迹数据。这些统计数据表明,解离的可能性密切跟踪(原生和非原生)单体间接触数量的减少和二聚体界面上水接触数量的增加;结合和分离可能性相等的过渡状态对应于一个具有相对较少的原生接触和许多非原生接触的相遇复合体。我们确定了四种途径的二聚体状态和量化其贡献的速度,以及他们的交换通过计算反应通量。我们表明,这两种途径和它们的交换程度可以理解为围绕三轴二聚体结构的旋转。我们的研究结果提供了胰岛素类似物动力学的见解,更一般地说,如何表征复杂的多途径过程。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
5.80
自引率
9.10%
发文量
965
审稿时长
1.6 months
期刊介绍: An essential criterion for acceptance of research articles in the journal is that they provide new physical insight. Please refer to the New Physical Insights virtual issue on what constitutes new physical insight. Manuscripts that are essentially reporting data or applications of data are, in general, not suitable for publication in JPC B.
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