Ali Ahmed A A I, Dorbath Emanuel, Stock Gerhard
Biomolecular Dynamics, Institute of Physics, University of Freiburg, 79104 Freiburg, Germany.
J Chem Theory Comput. 2024 Dec 10;20(23):10731-10739. doi: 10.1021/acs.jctc.4c01188. Epub 2024 Nov 22.
Describing the puzzling phenomenon of long-range communication between distant protein sites, allostery is of paramount importance in biomolecular regulation and signal transduction. It is commonly assumed to arise from a conformational rearrangement of the protein, although the underlying dynamical process has remained largely elusive. This study introduces a dynamical model of allosteric communication based on "contact clusters"─localized groups of highly correlated contacts that facilitate interactions between secondary structures. The model shows that allostery involves a multistep process with cooperative contact changes within clusters and communication between distant clusters mediated by rigid secondary structures. Considering time-dependent experiments on a photoswitchable PDZ3 domain, extensive (in total ∼500 μs) molecular dynamics simulations are conducted that directly monitor the photoinduced allosteric transition. The structural reorganization is illustrated by the time evolution of the contact clusters and the ligand, which effects the nonlocal coupling between distant clusters. A time scale analysis reveals dynamics from nano- to microseconds, which are in excellent agreement with the experimentally measured time scales. While the simulation of larger systems may require enhanced sampling techniques, it is expected that the general picture of allostery mediated by communicating contact clusters will still be applicable.
变构作用描述了远距离蛋白质位点之间令人费解的长程通信现象，在生物分子调节和信号转导中至关重要。通常认为它源于蛋白质的构象重排，尽管其潜在的动力学过程在很大程度上仍然难以捉摸。本研究引入了一种基于“接触簇”的变构通信动力学模型，“接触簇”是高度相关接触的局部化组，有助于二级结构之间的相互作用。该模型表明，变构作用涉及一个多步骤过程，其中簇内存在协同接触变化，并且由刚性二级结构介导远距离簇之间的通信。考虑到对可光开关的PDZ3结构域进行的时间相关实验，进行了广泛的（总计约500微秒）分子动力学模拟，直接监测光诱导的变构转变。接触簇和配体的时间演化说明了结构重组，这影响了远距离簇之间的非局部耦合。时间尺度分析揭示了从纳秒到微秒的动力学，这与实验测量的时间尺度非常吻合。虽然模拟更大的系统可能需要增强采样技术，但预计由通信接触簇介导的变构作用的总体情况仍然适用。
