期刊
JOURNAL OF THEORETICAL & COMPUTATIONAL CHEMISTRY
卷 8, 期 6, 页码 1265-1279出版社
WORLD SCIENTIFIC PUBL CO PTE LTD
DOI: 10.1142/S0219633609005313
关键词
HIV-1 protease; quantum mechanics (QM); MFCC; CPCM; free energy
资金
- National Natural Science Foundation of China [20803034]
- National Basic Research Program of China [2004CB719901]
- National Committee of Science Foundation [20773060]
HIV-1 protease (PR) is a primary target for anti-HIV therapeutics. A well conserved water molecule, denoted as W301, is found in almost all the crystallographic structures of PR/inhibitor complexes and it plays an important role in PR/inhibitor binding. As the PR/inhibitor interaction depends on the ionization state of the cleavage site which contains an aspartyl dyad (Asp25/Asp25'), the determination of the protonation states of aspartyl dyad in PR may be essential for drug design. In this study, a linear scaling quantum mechanical method, molecular fragmentation with conjugate caps (MFCC), is used for interaction study of PR/ABT-538 and W301 at four different monoprotonation states of the Asp25/Asp25'. Combined method of MFCC and conductor-like polarizable continuum model (CPCM) is applied in binding affinity calculation for four minimum energy structures which are extracted from four different molecular dynamics trajectories corresponding to four different monoprotonation states of Asp25/Asp25'. Our result is
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