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.

Kwanghoon Jeong

Spencer C. Guo

Sammy Allaw

Aaron R. Dinner

The Journal of Physical Chemistry B

期刊接受研究文章的一个基本标准是它们提供了新的物理见解。请参阅 NEW PHYSICAL INSIGHTS 虚拟问题，了解什么是新的物理洞察力。本质上报告数据或数据应用的手稿通常不适合在 JPC B 中发表。

The Journal of Physical Chemistry B accepts research articles based on the fundamental criterion of providing new physical insights. For what constitutes new physical insights, please refer to the NEW PHYSICAL INSIGHTS virtual issue. Manuscripts that primarily report data or data applications are generally not suitable for publication in the Journal of Physical Chemistry B.

《Journal of Physical Chemistry B》期刊接受研究文章的基本标准是提供新的物理见解。有关什么是新的物理洞察力，请参阅 NEW PHYSICAL INSIGHTS 虚拟问题。一般来说，仅报告数据或数据应用的手稿通常不适合在《Journal of Physical Chemistry B》上发表。

Category	Quartile
化学	2
化学, 物理化学	3

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

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