Computational study of bindings of HL9, a nonapeptide fragment of human lysozyme, to HIV-1 fusion protein gp41

• Published in: Bioorganic & medicinal chemistry letters 2011-03, Vol.21 (6), p.1607-1611
• Main Authors: Hartono, Yossa Dwi, Lee, Angelina Noviani, Lee-Huang, Sylvia, Zhang, Dawei
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Biological and medical sciences; energy; Fundamental and applied biological sciences. Psychology; glycoproteins; HIV Envelope Protein gp41 - metabolism; HIV-1 gp41; HL9; Human immunodeficiency virus 1; Human lysozyme; Humans; hydrophobicity; Interactions. Associations; Intermolecular phenomena; lysozyme; membrane fusion; Models, Molecular; Molecular biophysics; molecular dynamics; Molecular Sequence Data; Muramidase - chemistry; Muramidase - metabolism; Peptide Fragments - metabolism; peptide libraries; Protein Binding
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2011.01.121

HL9 is a nonapeptide fragment of human lysozyme which has been shown to have anti-HIV-1 activity in nanomolar concentration. This study aims to explain this inhibitory activity by using molecular dynamics (MD) simulation, focusing on the ectodomain of gp41, the envelope glycoprotein of HIV-1 crucial to membrane fusion. It was found that in HL9, two Trp residues separated by two others occupy the conserved hydrophobic pocket on gp41 and thus inhibit fusion in dominant-negative manner. Detailed HL9-gp41 binding interactions and free energies of binding were obtained through MD simulation and solvated interaction energies (SIE) calculation, giving a binding free energy of −8.25 kcal/mol which is in close agreement with the experimental value of −9.96 kcal/mol. Since C-helical region (C34) of gp41 also has two Trp residues separated by two others, this arrangement may be generalised and used to scan peptide library and to find those having similar manner of inhibition.