Tóth Gergely, Borics Attila
Locus Pharmaceuticals, Four Valley Square, 512 Township Line Rd., Blue Bell, PA 19422, USA.
J Mol Graph Model. 2006 May;24(6):465-74. doi: 10.1016/j.jmgm.2005.08.008. Epub 2005 Sep 26.
The active site of aspartic proteases, such as HIV-1 protease (PR), is covered by one or more flaps, which restrict access to the active site. For HIV-1 PR, X-ray diffraction studies suggested that in the free enzyme the two flaps are packed onto each other loosely in a semi-open conformation, while molecular dynamics (MD) studies observed that the flaps can also separate into open conformations. In this study, the mechanism of flap opening and the structure and dynamics of HIV-1 PR with semi-open and open flap conformations were investigated using molecular dynamics simulations. The flaps showed complex dynamic behavior as two distinct mechanisms of flap opening and various stable flap conformations (semi-open, open and curled) were observed during the simulations. A network of weakly polar interactions between the flaps were proposed to be responsible for stabilizing the semi-open flap conformation. It is hypothesized that such interactions could be responsible for making flap opening a highly sensitive gating mechanism which control access to the active site.
天冬氨酸蛋白酶的活性位点，如HIV-1蛋白酶（PR），被一个或多个瓣片覆盖，这些瓣片限制了对活性位点的 access。对于HIV-1 PR，X射线衍射研究表明，在游离酶中，两个瓣片以半开放构象彼此松散堆积，而分子动力学（MD）研究观察到瓣片也可以分离成开放构象。在本研究中，使用分子动力学模拟研究了瓣片打开的机制以及具有半开放和开放瓣片构象的HIV-1 PR的结构和动力学。瓣片表现出复杂的动态行为，因为观察到瓣片打开的两种不同机制以及在模拟过程中各种稳定的瓣片构象（半开放、开放和卷曲）。提出瓣片之间的弱极性相互作用网络负责稳定半开放瓣片构象。据推测，这种相互作用可能使瓣片打开成为一种高度敏感的门控机制，控制对活性位点的 access。
