PMID- 35054509
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20220716
IS  - 2075-1729 (Print)
IS  - 2075-1729 (Electronic)
IS  - 2075-1729 (Linking)
VI  - 12
IP  - 1
DP  - 2022 Jan 13
TI  - Ritonavir and xk263 Binding-Unbinding with HIV-1 Protease: Pathways, Energy and 
      Comparison.
LID - 10.3390/life12010116 [doi]
LID - 116
AB  - Understanding non-covalent biomolecular recognition, which includes drug-protein 
      bound states and their binding/unbinding processes, is of fundamental importance 
      in chemistry, biology, and medicine. Fully revealing the factors that govern the 
      binding/unbinding processes can further assist in designing drugs with desired 
      binding kinetics. HIV protease (HIVp) plays an integral role in the HIV life 
      cycle, so it is a prime target for drug therapy. HIVp has flexible flaps, and the 
      binding pocket can be accessible by a ligand via various pathways. Comparing 
      ligand association and dissociation pathways can help elucidate the 
      ligand-protein interactions such as key residues directly involved in the 
      interaction or specific protein conformations that determine the binding of a 
      ligand under certain pathway(s). Here, we investigated the ligand unbinding 
      process for a slow binder, ritonavir, and a fast binder, xk263, by using unbiased 
      all-atom accelerated molecular dynamics (aMD) simulation with a re-seeding 
      approach and an explicit solvent model. Using ritonavir-HIVp and xk263-HIVp 
      ligand-protein systems as cases, we sampled multiple unbinding pathways for each 
      ligand and observed that the two ligands preferred the same unbinding route. 
      However, ritonavir required a greater HIVp motion to dissociate as compared with 
      xk263, which can leave the binding pocket with little conformational change of 
      HIVp. We also observed that ritonavir unbinding pathways involved residues which 
      are associated with drug resistance and are distal from catalytic site. Analyzing 
      HIVp conformations sampled during both ligand-protein binding and unbinding 
      processes revealed significantly more overlapping HIVp conformations for 
      ritonavir-HIVp rather than xk263-HIVp. However, many HIVp conformations are 
      unique in xk263-HIVp unbinding processes. The findings are consistent with 
      previous findings that xk263 prefers an induced-fit model for binding and 
      unbinding, whereas ritonavir favors a conformation selection model. This study 
      deepens our understanding of the dynamic process of ligand unbinding and provides 
      insights into ligand-protein recognition mechanisms and drug discovery.
FAU - Sun, Jianan
AU  - Sun J
AD  - Environmental Toxicology Graduate Program, University of California, Riverside, 
      CA 92521, USA.
FAU - Raymundo, Mark Anthony V
AU  - Raymundo MAV
AD  - Department of Chemistry, University of California, Riverside, CA 92521, USA.
FAU - Chang, Chia-En A
AU  - Chang CA
AUID- ORCID: 0000-0002-6504-8529
AD  - Environmental Toxicology Graduate Program, University of California, Riverside, 
      CA 92521, USA.
AD  - Department of Chemistry, University of California, Riverside, CA 92521, USA.
LA  - eng
GR  - R01 GM109045/GM/NIGMS NIH HHS/United States
GR  - GM-109045/NH/NIH HHS/United States
PT  - Journal Article
DEP - 20220113
PL  - Switzerland
TA  - Life (Basel)
JT  - Life (Basel, Switzerland)
JID - 101580444
PMC - PMC8779838
OTO - NOTNLM
OT  - drug design
OT  - energy barrier
OT  - enhanced sampling
OT  - ligand-protein recognition
OT  - residence time
COIS- The authors declare no conflict of interest.
EDAT- 2022/01/22 06:00
MHDA- 2022/01/22 06:01
PMCR- 2022/01/13
CRDT- 2022/01/21 01:08
PHST- 2021/12/10 00:00 [received]
PHST- 2022/01/04 00:00 [revised]
PHST- 2022/01/10 00:00 [accepted]
PHST- 2022/01/21 01:08 [entrez]
PHST- 2022/01/22 06:00 [pubmed]
PHST- 2022/01/22 06:01 [medline]
PHST- 2022/01/13 00:00 [pmc-release]
AID - life12010116 [pii]
AID - life-12-00116 [pii]
AID - 10.3390/life12010116 [doi]
PST - epublish
SO  - Life (Basel). 2022 Jan 13;12(1):116. doi: 10.3390/life12010116.