Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, Illinois 60637, USA.
J Am Chem Soc. 2010 Jan 27;132(3):1010-7. doi: 10.1021/ja905671x.
The pathways of diffusion of a CO molecule inside a myoglobin protein and toward the solvent are investigated. Specifically, the three-dimensional potential of mean force (PMF or free energy) of the CO molecule position inside the protein is calculated by using the single-sweep method in concert with fully resolved atomistic simulations in explicit solvent. The results are interpreted under the assumption that the diffusion of the ligand can be modeled as a navigation on the PMF in which the ligand hops between the PMF local minima following the minimum free energy paths (MFEPs) with rates set by the free energy barriers that need to be crossed. Here, all the local minima of the PMF, the MFEPs, and the barriers along them are calculated. The positions of the local minima are in good agreement with all the known binding cavities inside the protein, which indicates that these cavities may indeed serve as dynamical traps inside the protein and thereby influence the binding process. In addition, the MFEPs connecting the local PMF minima show a complicated network of possible pathways of exit of the dissociated CO starting from the primary docking site, in which the histidine gate is the closest exit from the binding site for the ligand but it is not the only possible one.
研究了 CO 分子在肌红蛋白蛋白质内和朝向溶剂的扩散途径。具体来说，使用单扫描方法与完全解析的溶剂中的原子模拟相结合，计算了 CO 分子在蛋白质内位置的三维平均力势（PMF 或自由能）。根据假设，即配体的扩散可以模拟为沿着 PMF 的导航，其中配体沿着最小自由能路径（MFEPs）跳跃，速率由需要跨越的自由能势垒确定。在这里，计算了所有 PMF 的局部最小值、MFEPs 和沿它们的势垒。局部最小值的位置与蛋白质内所有已知的结合腔很好地吻合，这表明这些腔实际上可能是蛋白质内的动态陷阱，从而影响结合过程。此外，连接局部 PMF 最小值的 MFEPs 显示了从主要对接位点开始的解离 CO 可能的出口途径的复杂网络，其中组氨酸门是配体从结合位点的最近出口，但不是唯一可能的出口。
