Does Antibody Stabilize the Ligand Binding in GP120 of HIV-1 Envelope Protein? Evidence from MD Simulation

Autor:	Vishnudatt Pandey, Kshatresh Dutta Dubey, Rakesh Tiwari, Shalini Yadav, Rajendra Prasad Ojha
Rok vydání:	2021
Předmět:	Flexibility (anatomy) Anti-HIV Agents Protein Conformation conformational mechanism Mutant Enthalpy Pharmaceutical Science HIV Infections HIV Antibodies HIV Envelope Protein gp120 Molecular Dynamics Simulation HIV-entry inhibitor 01 natural sciences Article Analytical Chemistry lcsh:QD241-441 03 medical and health sciences Molecular dynamics Piperidines lcsh:Organic chemistry 0103 physical sciences Drug Discovery medicine Humans Molecule Physical and Theoretical Chemistry Receptor 030304 developmental biology Oxalates MD simulations 0303 health sciences 010304 chemical physics Chemistry Organic Chemistry free energy calculations Substrate (chemistry) Isothermal titration calorimetry medicine.anatomical_structure Chemistry (miscellaneous) HIV-1 Biophysics Thermodynamics Molecular Medicine Protein Binding
Zdroj:	Molecules, Vol 26, Iss 239, p 239 (2021) Molecules Volume 26 Issue 1
ISSN:	1420-3049
DOI:	10.3390/molecules26010239
Popis:	CD4-mimetic HIV-1 entry inhibitors are small sized molecules which imitate similar conformational flexibility, in gp120, to the CD4 receptor. However, the mechanism of the conformational flexibility instigated by these small sized inhibitors is little known. Likewise, the effect of the antibody on the function of these inhibitors is also less studied. In this study, we present a thorough inspection of the mechanism of the conformational flexibility induced by a CD4-mimetic inhibitor, NBD-557, using Molecular Dynamics Simulations and free energy calculations. Our result shows the functional importance of Asn425 in substrate induced conformational dynamics in gp120. The MD simulations of Asn425Gly mutant provide a less dynamic gp120 in the presence of NBD-557 without incapacitating the binding enthalpy of NBD-557. The MD simulations of complexes with the antibody clearly show the enhanced affinity of NBD-557 due to the presence of the antibody, which is in good agreement with experimental Isothermal Titration Calorimetry results (Biochemistry2006, 45, 10973&ndash 10980).
Databáze:	OpenAIRE
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