Boutonnet Nathalie, Janssens Wouter, Boutton Carlo, Verschelde Jean-Luc, Heyndrickx Leo, Beirnaert Els, van der Groen Guido, Lasters Ignace
Algonomics NV, 9052 Ghent, Belgium.
J Virol. 2002 Aug;76(15):7595-606. doi: 10.1128/jvi.76.15.7595-7606.2002.
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.
有人提出，参与人类免疫缺陷病毒1型（HIV-1）进入靶细胞过程的HIV-1 gp41胞外结构域（e-gp41）至少以两种构象存在，即发夹前体中间体和融合活性发夹结构。为了获得更多关于e-gp41结构-序列关系的信息，我们通过计算机模拟进行了全单氨基酸替换分析，得到了每种构象的折叠兼容数据库（FCD）。FCD针对给定蛋白质中的每个残基位置包含一个列表，该列表评估该位置上20种天然氨基酸各自的能量兼容性（ECO）。我们的结果表明，FCD预测与经过充分验证的e-gp41序列所观察到的序列变异高度一致。数据显示，在最小ECO阈值为5千卡/摩尔时，FCD预测涵盖了约90%观察到的患者序列变异。在N螺旋位置与C螺旋残基堆积处的一些不一致的FCD预测表明，两个肽段的堆积可能涉及一些灵活性，并且可能归因于C螺旋结构域相对于N螺旋区域的方向改变。C螺旋中序列变异的允许性与FCD预测一致。N核心和三发夹FCD的比较表明，N螺旋可能比C螺旋对序列变异施加更多限制。尽管观察到的e-gp41序列包含许多多重突变，但我们基于单点突变的方法能够很好地预测e-gp41的天然序列变异性。
