The binding mode of fusion inhibitor T20 onto HIV-1 gp41 and relevant T20-resistant mechanisms explored by computational study. 2012

Su Qiu, and Hong Yi, and Jun Hu, and Zhijian Cao, and Yingliang Wu, and Wenxin Li
State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, P.R. China.

Enfuvirtide (T20), the first FDA approved fusion inhibitor for HIV-1/AIDS, displayed outstanding effects of fusion inhibition by binding to the envelope glycoprotein gp41. But with the continuous emergence of T20-resistant mutations, the exploration of T20's binding mechanism onto gp41 wild type (WT) and the related resistance mechanism is needed. In this work, a complete structure model of gp41 including the fusion peptide (FP) and HR1 in complex with three molecules of T20 was obtained by structural modeling and molecular dynamics simulation (MDS). In this T20-gp41 model, the T20 hydrophobic C-terminal composed of the eight-residue sequence "WASLWNWF" formed unstructured coil instead of a helical structure, which enabled more residues of T20 to contact gp41 to exert its antiviral activity. Essential residues Trp155, Trp159, Trp161 and Phe162 of T20 formed strong vdW interactions with some hydrophobic cavities on the gp41, as never seen in other gp41 trimetric core structures. Based on the T20-gp41 model, seven corresponding structure models of T20-resistant mutants G36D, I37K, V38E, Q39H, Q41R, N43D and L45M were constructed and fully equilibrated by MDS. Most remarkably, the I37K and Q41R mutations led to collapse of the coiled coil structure, causing greatest change in binding energy. Also notably, the V38E and N43D mutations hindered the binding of T20 through electrostatic repulsion and thus also resulted in dramatic change in binding energy. Besides, mutations G36D, Q39H and L45M only caused minor conformational and energetic changes. In all, these results could provide new clues for the design of T20-like peptide inhibitors to target the T20-resistant virus.

UI MeSH Term Description Entries
D008962 Models, Theoretical Theoretical representations that simulate the behavior or activity of systems, processes, or phenomena. They include the use of mathematical equations, computers, and other electronic equipment. Experimental Model,Experimental Models,Mathematical Model,Model, Experimental,Models (Theoretical),Models, Experimental,Models, Theoretic,Theoretical Study,Mathematical Models,Model (Theoretical),Model, Mathematical,Model, Theoretical,Models, Mathematical,Studies, Theoretical,Study, Theoretical,Theoretical Model,Theoretical Models,Theoretical Studies
D008969 Molecular Sequence Data Descriptions of specific amino acid, carbohydrate, or nucleotide sequences which have appeared in the published literature and/or are deposited in and maintained by databanks such as GENBANK, European Molecular Biology Laboratory (EMBL), National Biomedical Research Foundation (NBRF), or other sequence repositories. Sequence Data, Molecular,Molecular Sequencing Data,Data, Molecular Sequence,Data, Molecular Sequencing,Sequencing Data, Molecular
D010446 Peptide Fragments Partial proteins formed by partial hydrolysis of complete proteins or generated through PROTEIN ENGINEERING techniques. Peptide Fragment,Fragment, Peptide,Fragments, Peptide
D011485 Protein Binding The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific protein-binding measures are often used as assays in diagnostic assessments. Plasma Protein Binding Capacity,Binding, Protein
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000077560 Enfuvirtide A synthetic 36-amino acid peptide that corresponds to the heptad repeat sequence of HIV-1 gp41. It blocks HIV cell fusion and viral entry and is used with other anti-retrovirals for combination therapy of HIV INFECTIONS and AIDS. DP 178,DP-178,DP178,Fuzeon,Pentafuside,Peptide T20,T20 Peptide,T20, Peptide
D015497 HIV-1 The type species of LENTIVIRUS and the etiologic agent of AIDS. It is characterized by its cytopathic effect and affinity for the T4-lymphocyte. Human immunodeficiency virus 1,HIV-I,Human Immunodeficiency Virus Type 1,Immunodeficiency Virus Type 1, Human
D015700 HIV Envelope Protein gp41 Transmembrane envelope protein of the HUMAN IMMUNODEFICIENCY VIRUS which is encoded by the HIV env gene. It has a molecular weight of 41,000 and is glycosylated. The N-terminal part of gp41 is thought to be involved in CELL FUSION with the CD4 ANTIGENS of T4 LYMPHOCYTES, leading to syncytial formation. Gp41 is one of the most common HIV antigens detected by IMMUNOBLOTTING. Envelope Protein gp41, HIV,HIV Transmembrane Protein gp41,HTLV-III gp41,env Protein gp41, HIV,gp41(HIV),gp41 Envelope Protein, HIV
D017434 Protein Structure, Tertiary The level of protein structure in which combinations of secondary protein structures (ALPHA HELICES; BETA SHEETS; loop regions, and AMINO ACID MOTIFS) pack together to form folded shapes. Disulfide bridges between cysteines in two different parts of the polypeptide chain along with other interactions between the chains play a role in the formation and stabilization of tertiary structure. Tertiary Protein Structure,Protein Structures, Tertiary,Tertiary Protein Structures
D023581 HIV Fusion Inhibitors Inhibitors of the fusion of HIV to host cells, preventing viral entry. This includes compounds that block attachment of HIV ENVELOPE PROTEIN GP120 to CD4 RECEPTORS. Fusion Inhibitors, HIV,HIV Cell Fusion Inhibitor,HIV Entry Inhibitor,HIV Entry Inhibitors,HIV Fusion Inhibitor,HIV Fusion Protein Inhibitor,HIV Cell Fusion Inhibitors,HIV Fusion Protein Inhibitors,Entry Inhibitor, HIV,Entry Inhibitors, HIV,Fusion Inhibitor, HIV,Inhibitor, HIV Entry,Inhibitor, HIV Fusion

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