title: Thermodynamic dissection of a low affinity protein-protein interface involved in human immunodeficiency virus assembly.
abstract: Homo-dimerization of the capsid protein CA of human immunodeficiency virus through its C-terminal domain constitutes an early crucial step in the virion assembly pathway and a potential target for antiviral inhibitors. We have truncated to alanine the 20 amino acid side chains per monomer that participate in intersubunit contacts at the CA dimer interface and analyzed their individual energetic contribution to protein association and stability. About half of the side chains in the contact epitope are critically involved in the energetic epitope as their truncation essentially prevented dimerization. However, dimerization affinity is kept low partly because of the presence of interfacial side chains whose individual truncation improves affinity by 2-20-fold. Many side chains at the interface are energetically important also for the folding of a monomeric intermediate and for its conformational rearrangement during dimerization. The thermodynamic description of this low affinity interface (dissociation constant of approximately 10 microm) was compared with those obtained for the other protein-protein interfaces, nearly all of them of much higher affinity, that have been systematically analyzed by mutation. The results reveal differences that may have been evolutionary selected and that may be exploited for the design of an effective interfacial inhibitor of human immunodeficiency virus assembly.
authors.affiliation: Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: del Alamo
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Neira
authors.forename: Mauricio G
authors.initials: MG
authors.lastname: Mateu
mesh_terms: D000409:Alanine / Q000737:chemistry; D036022:Capsid Proteins / Q000737:chemistry*; D002850:Chromatography, Gel; D002942:Circular Dichroism; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D000939:Epitopes; D006678:HIV / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology*; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D013050:Spectrometry, Fluorescence; D013816:Thermodynamics; D019065:Virus Assembly
chemical_list: D036022:Capsid Proteins; D000939:Epitopes; D000409:Alanine