How Mutations Can Resist Drug Binding yet Keep HIV-1 Protease Functional

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• Human immunodeficiency virus-1 (HIV-1) protease is a critical target for acquired immune deficiency syndrome (AIDS) therapies.
• Approved drugs face challenges due to the emergence of drug-resistant protease mutants that retain enzymatic activity.
• Understanding resistance mechanisms is vital for developing effective treatment strategies.

Purpose of the Study:

• To investigate how mutations in HIV-1 protease confer drug resistance while preserving enzymatic function.
• To elucidate the molecular mechanisms underlying the binding of substrates and drugs to wild-type and mutant proteases.

Main Methods:

• Utilized large-scale molecular dynamics simulations.
• Analyzed interactions between wild-type and mutant HIV-1 proteases with FDA-approved drugs and various substrate sequences.

Main Results:

• Substrate binding to proteases involves extensive H-bonding, unaffected by mutations.
• Drug binding primarily relies on hydrophobic interactions with active site and flap residues, which are sensitive to mutations.
• Mutations significantly weaken drug binding affinity due to altered hydrophobic interactions and fewer binding sites compared to substrates.

Conclusions:

• HIV-1 protease mutations confer drug resistance by disrupting drug-binding interactions, not substrate interactions.
• Identifying key residues in protease active sites and flaps involved in ligand recognition is crucial.
• Findings can guide the design of novel HIV-1 protease inhibitors that overcome existing resistance mechanisms.