title: Comparison of predicted scaffold-compatible sequence variation in the triple-hairpin structure of human imunodeficiency virus type 1 gp41 with patient data.
abstract: It has been proposed that the ectodomain of human immunodeficiency virus type 1 (HIV-1) gp41 (e-gp41), involved in HIV entry into the target cell, exists in at least two conformations, a pre-hairpin intermediate and a fusion-active hairpin structure. To obtain more information on the structure-sequence relationship in e-gp41, we performed in silico a full single-amino-acid substitution analysis, resulting in a Fold Compatible Database (FCD) for each conformation. The FCD contains for each residue position in a given protein a list of values assessing the energetic compatibility (ECO) of each of the 20 natural amino acids at that position. Our results suggest that FCD predictions are in good agreement with the sequence variation observed for well-validated e-gp41 sequences. The data show that at a minECO threshold value of 5 kcal/mol, about 90% of the observed patient sequence variation is encompassed by the FCD predictions. Some inconsistent FCD predictions at N-helix positions packing against residues of the C helix suggest that packing of both peptides may involve some flexibility and may be attributed to an altered orientation of the C-helical domain versus the N-helical region. The permissiveness of sequence variation in the C helices is in agreement with FCD predictions. Comparison of N-core and triple-hairpin FCDs suggests that the N helices may impose more constraints on sequence variation than the C helices. Although the observed sequences of e-gp41 contain many multiple mutations, our method, which is based on single-point mutations, can predict the natural sequence variability of e-gp41 very well.
authors.affiliation: Algonomics NV, 9052 Ghent, Belgium.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Boutonnet
authors.forename: Wouter
authors.initials: W
authors.lastname: Janssens
authors.forename: Carlo
authors.initials: C
authors.lastname: Boutton
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Verschelde
authors.forename: Leo
authors.initials: L
authors.lastname: Heyndrickx
authors.forename: Els
authors.initials: E
authors.lastname: Beirnaert
authors.forename: Guido
authors.initials: G
authors.lastname: van der Groen
authors.forename: Ignace
authors.initials: I
authors.lastname: Lasters
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D016208:Databases, Factual; D014644:Genetic Variation; D005838:Genotype; D015700:HIV Envelope Protein gp41 / Q000737:chemistry / Q000235:genetics*; D015658:HIV Infections / Q000821:virology; D015497:HIV-1 / Q000145:classification* / Q000235:genetics / Q000302:isolation & purification; D006801:Humans; D008561:Membrane Fusion; D008969:Molecular Sequence Data; D010641:Phenotype; D011487:Protein Conformation; D017510:Protein Folding
chemical_list: D015700:HIV Envelope Protein gp41