Chemical Sciences Laboratory, Department of Chemistry and Biochemistry and National High Magnetic Field Laboratory, Florida State University, Tallahassee, Florida, USA.
PLoS Comput Biol. 2011 Apr;7(4):e1002035. doi: 10.1371/journal.pcbi.1002035. Epub 2011 Apr 21.
Elucidation of the mechanism of biomacromolecular recognition events has been a topic of intense interest over the past century. The inherent dynamic nature of both protein and ligand molecules along with the continuous reshaping of the energy landscape during the binding process renders it difficult to characterize this process at atomic detail. Here, we investigate the recognition dynamics of ubiquitin via microsecond all-atom molecular dynamics simulation providing both thermodynamic and kinetic information. The high-level of consistency found with respect to experimental NMR data lends support to the accuracy of the in silico representation of the conformational substates and their interconversions of free ubiquitin. Using an energy-based reweighting approach, the statistical distribution of conformational states of ubiquitin is monitored as a function of the distance between ubiquitin and its binding partner Hrs-UIM. It is found that extensive and dense sampling of conformational space afforded by the µs MD trajectory is essential for the elucidation of the binding mechanism as is Boltzmann sampling, overcoming inherent limitations of sparsely sampled empirical ensembles. The results reveal a population redistribution mechanism that takes effect when the ligand is at intermediate range of 1-2 nm from ubiquitin. This mechanism, which may be depicted as a superposition of the conformational selection and induced fit mechanisms, also applies to other binding partners of ubiquitin, such as the GGA3 GAT domain.
阐明生物大分子识别事件的机制是过去一个世纪以来人们关注的热点。由于蛋白质和配体分子固有的动态特性以及在结合过程中能量景观的不断重塑，使得很难在原子细节上描述这个过程。在这里，我们通过微秒全原子分子动力学模拟研究了泛素的识别动力学，提供了热力学和动力学信息。与实验 NMR 数据高度一致，这支持了自由泛素构象亚稳态及其相互转化的计算表示的准确性。使用基于能量的再加权方法，监测构象状态的统计分布作为泛素与其结合伴侣 Hrs-UIM 之间距离的函数。结果表明，µs MD 轨迹提供的构象空间的广泛和密集采样对于阐明结合机制是必不可少的，这就克服了经验集合稀疏采样的固有局限性。结果揭示了一种当配体处于 1-2nm 的中间范围时起作用的种群再分布机制。这种机制可以被描绘为构象选择和诱导契合机制的叠加，也适用于泛素的其他结合伴侣，如 GGA3 GAT 结构域。
