Substrate Binding Mechanism of HIV-1 Protease from Explicit-Solvent Atomistic Simulations

被引:117
作者
Pietrucci, Fabio [1 ]
Marinelli, Fabrizio [1 ]
Carloni, Paolo [1 ]
Laio, Alessandro [1 ]
机构
[1] SISSA, Int Sch Adv Studies, Via Beirut 2-4, I-34014 Trieste, Italy
关键词
HUMAN-IMMUNODEFICIENCY-VIRUS; FREE-ENERGY LANDSCAPE; PARTICLE MESH EWALD; MOLECULAR-DYNAMICS; INHIBITORS; RESISTANCE; FLEXIBILITY; RECOGNITION; COMPLEX; WATER;
D O I
10.1021/ja903045y
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
The binding mechanism of a peptide substrate (Thr-lle-Met-Met-Gln-Arg, cleavage site p2-NC of the viral polyprotein) to wild-type HIV-1 protease has been investigated by 1.6 mu s biased all-atom molecular dynamics simulations in explicit water. The configuration space has been explored biasing seven reaction coordinates by the bias-exchange metadynamics technique. The structure of the Michaelis complex is obtained starting from the substrate outside the enzyme within a backbone rmsd of 0.9 angstrom. The calculated free energy of binding is -6 kcal/mol, and the kinetic constants for association and dissociation are 1.3 x 10(6) M-1 s(-1) and 57 s(-1), respectively, consistent with experiments. In the main binding pathway, the flaps of the protease do not open sizably. The substrate slides inside the enzyme cavity from the tight lateral channel. This may contrast with the natural polyprotein substrate which is expected to bind by opening the flaps. Thus, mutations might influence differently the binding kinetics of peptidomimetic ligands and of the natural substrate.
引用
收藏
页码:11811 / 11818
页数:8
相关论文
共 64 条
[1]   An improved relaxed complex scheme for receptor flexibility in computer-aided drug design [J].
Amaro, Rommie E. ;
Baron, Riccardo ;
McCammon, J. Andrew .
JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN, 2008, 22 (09) :693-705
[2]  
[Anonymous], OECHEM VERS 1 3 4
[3]  
[Anonymous], SCI STKE
[4]   Electrostatics of nanosystems: Application to microtubules and the ribosome [J].
Baker, NA ;
Sept, D ;
Joseph, S ;
Holst, MJ ;
McCammon, JA .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2001, 98 (18) :10037-10041
[5]   Absolute free energies of binding of peptide analogs to the HIV-1 protease from molecular dynamics simulations [J].
Bartels, C ;
Widmer, A ;
Ehrhardt, C .
JOURNAL OF COMPUTATIONAL CHEMISTRY, 2005, 26 (12) :1294-1305
[6]   MOLECULAR-DYNAMICS WITH COUPLING TO AN EXTERNAL BATH [J].
BERENDSEN, HJC ;
POSTMA, JPM ;
VANGUNSTEREN, WF ;
DINOLA, A ;
HAAK, JR .
JOURNAL OF CHEMICAL PHYSICS, 1984, 81 (08) :3684-3690
[7]   From A to B in free energy space [J].
Branduardi, Davide ;
Gervasio, Francesco Luigi ;
Parrinello, Michele .
JOURNAL OF CHEMICAL PHYSICS, 2007, 126 (05)
[8]   Free-energy landscape for β hairpin folding from combined parallel tempering and metadynamics [J].
Bussi, Giovanni ;
Gervasio, Francesco Luigi ;
Laio, Alessandro ;
Parrinello, Michele .
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2006, 128 (41) :13435-13441
[9]   Binding pathways of ligands to HIV-1 protease: Coarse-grained and atomistic simulations [J].
Chang, Chia-En A. ;
Trylska, Joanna ;
Tozzini, Valentina ;
McCammon, J. Andrew .
CHEMICAL BIOLOGY & DRUG DESIGN, 2007, 69 (01) :5-13
[10]   PARTICLE MESH EWALD - AN N.LOG(N) METHOD FOR EWALD SUMS IN LARGE SYSTEMS [J].
DARDEN, T ;
YORK, D ;
PEDERSEN, L .
JOURNAL OF CHEMICAL PHYSICS, 1993, 98 (12) :10089-10092