Piana Stefano, Carloni Paolo, Parrinello Michele
Scuola Internazionale Superiore di Studi Avanzati and Istituto Nazionale di Fisica per la Materia, Via Beirut 2-4, 34014 Trieste, Italy.
J Mol Biol. 2002 May 31;319(2):567-83. doi: 10.1016/S0022-2836(02)00301-7.
The emergence of compensatory drug-resistant mutations in HIV-1 protease challenges the common view of the reaction mechanism of this enzyme. Here, we address this issue by performing classical and ab initio molecular dynamics simulations (MD) on a complex between the enzyme and a peptide substrate. The classical MD calculation reveals large-scale protein motions involving the flaps and the cantilever. These motions modulate the conformational properties of the substrate at the cleavage site. The ab initio calculations show in turn that substrate motion modulates the activation free energy barrier of the enzymatic reaction dramatically. Thus, the catalytic power of the enzyme does not arise from the presence of a pre-organized active site but from the protein mechanical fluctuations. The implications of this finding for the emergence of drug-resistance are discussed.
HIV-1蛋白酶中补偿性耐药突变的出现挑战了对该酶反应机制的传统观点。在此，我们通过对该酶与肽底物的复合物进行经典和从头算分子动力学模拟（MD）来解决这一问题。经典MD计算揭示了涉及瓣片和悬臂的大规模蛋白质运动。这些运动调节了切割位点处底物的构象性质。反过来，从头算计算表明底物运动显著调节了酶促反应的活化自由能垒。因此，酶的催化能力并非源于预先组织好的活性位点的存在，而是源于蛋白质的机械波动。讨论了这一发现对耐药性出现的影响。
