Perryman Alexander L, Lin Jung-Hsin, McCammon J Andrew
Howard Hughes Medical Institute, Center for Theoretical Biological Physics, and Department of Pharmacology, University of California at San Diego, La Jolla, 92093-0365, USA.
Biopolymers. 2006 Jun 15;82(3):272-84. doi: 10.1002/bip.20497.
To test the anticorrelated relationship that was recently displayed in conventional molecular dynamics (MD) simulations, several different restrained MD simulations on a wild type and on the V82F/I84V drug-resistant mutant of HIV-1 protease were performed. This anticorrelated relationship refers to the observation that compression of the peripheral ear-to-cheek region of HIV protease (i.e., the elbow of the flap to the fulcrum and the cantilever) occurred as the active site flaps were opening, and, conversely, expansion of that ear-to-cheek region occurred as both flaps were closing. An additional examination of this anticorrelated relationship was necessary to determine whether it can be harnessed in a useful manner. Consequently, six different MD experiments were performed that incorporated pairwise distance restraints in that ear-to-cheek region (i.e., the distance between the alpha-carbons of Gly40 and Gln61 was restrained to either 7.7 or 10.5 A, in both monomers). Pushing the backbones of the ear and the cheek regions away from each other slightly did force the flaps that guard the active site to remain closed in both the wild type and the mutant systems-even though there were no ligands in the active sites. Thus, these restrained MD simulations provided evidence that the anticorrelated relationship can be exploited to affect the dynamic behavior of the flaps that guard the active site of HIV-1 protease. These simulations supported our hypothesis of the mechanism governing flap motion, and they are the first step towards validating that peripheral surface as a new target for drug design.
为了测试最近在传统分子动力学（MD）模拟中显示的反相关关系，我们对野生型和HIV-1蛋白酶的V82F/I84V耐药突变体进行了几种不同的受限MD模拟。这种反相关关系指的是观察到，在活性位点的瓣片打开时，HIV蛋白酶外周耳到颊区域（即瓣片的肘部到支点和悬臂）发生压缩，相反，当两个瓣片关闭时，该耳到颊区域发生扩张。对这种反相关关系进行额外研究，以确定是否可以以有用的方式利用它。因此，我们进行了六个不同的MD实验，在该耳到颊区域纳入了成对距离限制（即，在两个单体中，Gly40和Gln61的α-碳原子之间的距离被限制为7.7或10.5 Å）。将耳和颊区域的主链彼此稍微推开，确实迫使保护活性位点的瓣片在野生型和突变体系统中都保持关闭——即使活性位点中没有配体。因此，这些受限MD模拟提供了证据，表明可以利用反相关关系来影响保护HIV-1蛋白酶活性位点的瓣片的动态行为。这些模拟支持了我们关于瓣片运动机制的假设，并且它们是朝着将外周表面验证为药物设计新靶点迈出的第一步。
