PMID- 28060481
OWN - NLM
STAT- MEDLINE
DCOM- 20170508
LR  - 20181113
IS  - 1520-4995 (Electronic)
IS  - 0006-2960 (Print)
IS  - 0006-2960 (Linking)
VI  - 56
IP  - 9
DP  - 2017 Mar 7
TI  - Mechanism of the Association Pathways for a Pair of Fast and Slow Binding Ligands 
      of HIV-1 Protease.
PG  - 1311-1323
LID - 10.1021/acs.biochem.6b01112 [doi]
AB  - Equilibrium constants, together with kinetic rate constants of binding, are key 
      factors in the efficacy and safety of drug compounds, informing drug design. 
      However, the association pathways of protein-ligand binding, which contribute to 
      their kinetic behaviors, are little understood. In this work, we used unbiased 
      all-atom molecular dynamics (MD) simulations with an explicit solvent model to 
      study the association processes of protein-ligand binding. Using the HIV protease 
      (HIVp)-xk263 and HIVp-ritonavir protein-ligand systems as cases, we observed that 
      ligand association is a multistep process involving diffusion, localization, and 
      conformational rearrangements of the protein, ligand, and water molecules. 
      Moreover, these two ligands preferred different routes of binding, which reflect 
      two well-known binding mechanisms: induced-fit and conformation selection models. 
      Our study shows that xk263 has a stronger capacity for desolvating surrounding 
      water molecules, thereby inducing a semiopen conformation of the HIVp flaps 
      (induced-fit model). In contrast, the slow dehydration characteristic of 
      ritonavir allows for gradual association with the binding pocket of HIVp when the 
      protein's flap conformation is fully open (conformation selection model). By 
      studying the mechanism of ligand association and understanding the role of 
      solvent molecules during the binding event, we can obtain a different perspective 
      on the mechanism of macromolecule recognition, providing insights into drug 
      discovery.
FAU - Huang, Yu-Ming M
AU  - Huang YM
AUID- ORCID: 0000-0003-3257-6170
AD  - Department of Chemistry, University of California, Riverside , Riverside, 
      California 92521, United States.
FAU - Raymundo, Mark Anthony V
AU  - Raymundo MA
AD  - Department of Chemistry, University of California, Riverside , Riverside, 
      California 92521, United States.
FAU - Chen, Wei
AU  - Chen W
AD  - Department of Chemistry, University of California, Riverside , Riverside, 
      California 92521, United States.
AD  - ChemConsulting LLC , Frederick, Maryland 21704, United States.
FAU - Chang, Chia-En A
AU  - Chang CA
AD  - Department of Chemistry, University of California, Riverside , Riverside, 
      California 92521, United States.
LA  - eng
GR  - P41 GM103712/GM/NIGMS NIH HHS/United States
GR  - R01 GM109045/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20170221
PL  - United States
TA  - Biochemistry
JT  - Biochemistry
JID - 0370623
RN  - 059QF0KO0R (Water)
RN  - EC 3.4.23.- (HIV Protease)
RN  - O3J8G9O825 (Ritonavir)
SB  - IM
MH  - HIV Protease/*chemistry/*metabolism
MH  - HIV-1/*enzymology
MH  - Kinetics
MH  - *Molecular Dynamics Simulation
MH  - Protein Binding
MH  - Protein Conformation
MH  - Ritonavir/metabolism
MH  - Water/metabolism
PMC - PMC5499997
MID - NIHMS866843
COIS- Notes The authors declare no competing financial interest.
EDAT- 2017/01/07 06:00
MHDA- 2017/05/10 06:00
PMCR- 2017/07/06
CRDT- 2017/01/07 06:00
PHST- 2017/01/07 06:00 [pubmed]
PHST- 2017/05/10 06:00 [medline]
PHST- 2017/01/07 06:00 [entrez]
PHST- 2017/07/06 00:00 [pmc-release]
AID - 10.1021/acs.biochem.6b01112 [doi]
PST - ppublish
SO  - Biochemistry. 2017 Mar 7;56(9):1311-1323. doi: 10.1021/acs.biochem.6b01112. Epub 
      2017 Feb 21.