NDLI: Why is Substrate Peptide Binding Unsusceptible to Multidrug-Resistant Mutations in HIV-1 Protease? A Structural and Energetic Analysis

Content Provider	Springer Nature Link
Author	Ni, Zhong Chen, Huayou Qi, Xianghui Jin, Rongzhong
Copyright Year	2013
Abstract	Understanding of the molecular mechanism and biological implication underlying the difference in binding of substrate peptides and small-molecule inhibitors to multidrug-resistant mutants of HIV-1 protease would help to develop new anti-HIV agents combating drug resistance. Here, an integration of rigorous quantum mechanics/molecular mechanics (QM/MM) analysis and empirical Poisson–Boltzmann/surface area (PB/SA) model is described to investigate the structural basis and energetic property of wild-type HIV-1 protease and its mutants in recognizing and binding with a wide variety of ligands, including the peptides derived from its cognate cleavage sites and the cleavage site variants as well as a number of FDA-approved protease inhibitors, attempting to explain why is substrate binding unsusceptible to most observed HIV-1 protease mutations. A preliminary test study demonstrates that the combined QM/MM–PB/SA scheme is able to effectively reproduce the relative ligand binding energy changes upon protease single- and double-mutations, albeit the absolute values appear to be different significantly between the calculated and experimental results. With the QM/MM–PB/SA calculations a complete mutation energy map of HIV-1 protease–ligand interactions is created, which unravels distinct affinity pictures of wild-type substrates, substrate variants and, particularly, the protease inhibitors bound to HIV-1 protease mutants, suggesting that, on the one hand, the evaluation pressure under anti-HIV chemotherapies addresses site-directed protease mutations that impair and undermine the intermolecular interactions specific to inhibitors but not substrates; on the other hand, co-evaluation of protease and its substrate peptides provides a more effective mechanism to avoid therapeutic surveillance. Further, nonbonded interaction analysis and computational alanine scanning reveal 12 key residues that is critical for substrate binding, from which the Asn25, Gly27, Ala28, Asp29 and Pro81 are identified that have not yet been found to cause drug resistance and hence would be the promising sites targeted by new protease inhibitors.
Starting Page	43
Ending Page	51
Page Count	9
File Format	PDF
ISSN	15733149
Journal	International Journal of Peptide Research and Therapeutics
Volume Number	20
Issue Number	1
e-ISSN	15733904
Language	English
Publisher	Springer Netherlands
Publisher Date	2013-08-28
Publisher Place	Dordrecht
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	HIV-1 protease Substrate peptide Inhibitor Multidrug resistance Biochemistry Animal Anatomy / Morphology / Histology Polymer Sciences Pharmaceutical Sciences/Technology Pharmacology/Toxicology Molecular Medicine
Content Type	Text
Resource Type	Article
Subject	Analytical Chemistry Drug Discovery Biochemistry Molecular Medicine Bioengineering

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