Interchain hydrophobic clustering promotes rigidity in HIV-1 protease flap dynamics: new insights from Molecular Dynamics

被引:2
作者
Meher, Biswa Ranjan [1 ,2 ]
Kumar, Mattaparthi Venkata Satish [3 ]
Bandyopadhyay, Pradipta [4 ]
机构
[1] Indian Inst Technol, Dept Biotechnol, Computat Biol Res Lab, Gauhati 781039, Assam, India
[2] Albany State Univ, Dept Nat Sci, Computat Chem Lab, Albany, GA 31705 USA
[3] Sastra Univ, Sch Chem & Biotechnol, Thanjavur 613401, Tamil Nadu, India
[4] Jawaharlal Nehru Univ, Sch Computat & Integrat Sci, Ctr Computat Biol & Bioinformat, New Delhi 110067, India
关键词
force field; flap dynamics; Molecular Dynamics simulation; HIV-1; protease; hydrophobic cluster; HUMAN-IMMUNODEFICIENCY-VIRUS; DRUG-RESISTANCE; FORCE-FIELDS; WILD-TYPE; SIMULATIONS; MUTATIONS; MECHANISM; FLEXIBILITY; INHIBITOR; SUBSTRATE;
D O I
10.1080/07391102.2013.795873
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The dynamics of HIV-1 protease (HIV-pr), a drug target for HIV infection, has been studied extensively by both computational and experimental methods. The flap dynamics of HIV-pr is considered to be more important for better ligand binding and enzymatic actions. Moreover, it has been demonstrated that the drug-induced mutations can change the flap dynamics of HIV-pr affecting the binding affinity of the ligands. Therefore, detailed understanding of flap dynamics is essential for designing better inhibitors. Previous computational investigations observed significant variation in the flap opening in nanosecond time scale indicating that the dynamics is highly sensitive to the simulation protocols. To understand the sensitivity of the flap dynamics on the force field and simulation protocol, molecular dynamics simulations of HIV-pr have been performed with two different AMBER force fields, ff99 and ff02. Two different trajectories (20 ns each) were obtained using the ff99 and ff02 force field. The results showed polarizable force field (ff02) make the flap tighter than the nonpolarizable force field (ff99). Some polar interactions and hydrogen bonds involving flap residues were found to be stronger with ff02 force field. The formation of interchain hydrophobic cluster (between flap tip of one chain and active site wall of another chain) was found to be dominant in the semi-open structures obtained from the simulations irrespective of the force field. It is proposed that an inhibitor, which will promote this interchain hydrophobic clustering, may make the flaps more rigid, and presumably the effect of mutation would be small on ligand binding.
引用
收藏
页码:899 / 915
页数:17
相关论文
共 45 条
[1]   Molecular Basis for Drug Resistance in HIV-1 Protease [J].
Ali, Akbar ;
Bandaranayake, Rajintha M. ;
Cai, Yufeng ;
King, Nancy M. ;
Kolli, Madhavi ;
Mittal, Seema ;
Murzycki, Jennifer F. ;
Nalam, Madhavi N. L. ;
Nalivaika, Ellen A. ;
Oezen, Ayseguel ;
Prabu-Jeyabalan, Moses M. ;
Thayer, Kelly ;
Schiffer, Celia A. .
VIRUSES-BASEL, 2010, 2 (11) :2509-2535
[2]   Drug resistance of HIV-1 protease against JE-2147:I47V mutation investigated by molecular dynamics simulation [J].
Bandyopadhyay, P ;
Meher, BR .
CHEMICAL BIOLOGY & DRUG DESIGN, 2006, 67 (02) :155-161
[3]   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
[4]   STRUCTURE AND PROPERTIES OF NEAT LIQUIDS USING NONADDITIVE MOLECULAR-DYNAMICS - WATER, METHANOL, AND N-METHYLACETAMIDE [J].
CALDWELL, JW ;
KOLLMAN, PA .
JOURNAL OF PHYSICAL CHEMISTRY, 1995, 99 (16) :6208-6219
[5]  
Case D.A., 2006, AMBER, V9
[6]   A 500-PS MOLECULAR-DYNAMICS SIMULATION STUDY OF INTERLEUKIN-1-BETA IN WATER - CORRELATION WITH NUCLEAR-MAGNETIC-RESONANCE SPECTROSCOPY AND CRYSTALLOGRAPHY [J].
CHANDRASEKHAR, I ;
CLORE, GM ;
SZABO, A ;
GRONENBORN, AM ;
BROOKS, BR .
JOURNAL OF MOLECULAR BIOLOGY, 1992, 226 (01) :239-250
[7]   Insights into drug resistance of mutations D30N and I50V to HIV-1 protease inhibitor TMC-114: Free energy calculation and molecular dynamic simulation [J].
Chen, Jianzhong ;
Zhang, Shaolong ;
Liu, Xinguo ;
Zhang, Qinggang .
JOURNAL OF MOLECULAR MODELING, 2010, 16 (03) :459-468
[8]   Molecular dynamics simulations of 14 HIV protease mutants in complexes with indinavir [J].
Chen, XF ;
Weber, IT ;
Harrison, RW .
JOURNAL OF MOLECULAR MODELING, 2004, 10 (5-6) :373-381
[9]   Molecular mechanical models for organic and biological systems going beyond the atom centered two body additive approximation: Aqueous solution free energies of methanol and N-methyl acetamide, nucleic acid base, and amide hydrogen bonding and chloroform/water partition coefficients of the nucleic acid bases [J].
Cieplak, P ;
Caldwell, J ;
Kollman, P .
JOURNAL OF COMPUTATIONAL CHEMISTRY, 2001, 22 (10) :1048-1057
[10]   Effects of the V82A and I54V mutations on the dynamics and ligand binding properties of HIV-1 protease [J].
Dirauf, Pia ;
Meiselbach, Heike ;
Sticht, Heinrich .
JOURNAL OF MOLECULAR MODELING, 2010, 16 (10) :1577-1583