Petit S, Brard F, Coquerel G, Perez G, Tron F
Laboratoire de Modélisation Moléculaire, IRCOF, IFRMP No. 23, Université de Rouen, Mont-Saint-Aignan, France.
J Comput Aided Mol Des. 1998 Mar;12(2):147-63. doi: 10.1023/a:1007937823079.
The value of comparative molecular modeling for elucidating structure-function relationships was demonstrated by analyzing six anti-nucleosome autoantibody variable fragments. Structural models were built using the automated procedure developed in the COMPOSER software, subsequently minimized with the AMBER force field, and validated according to several standard geometric and chemical criteria. Canonical class assignment from Chothia and Lesk's [Chottin and Lesk, J. Mol. Biol., 196 (1987) 901; Chothia et al., Nature, 342 (1989) 877] work was used as a supplementary validation tool for five of the six hypervariable loops. The analysis, based on the hypothesis that antigen binding could occur through electrostatic interactions, reveals a diversity of possible binding mechanisms of anti-nucleosome or anti-histone antibodies to their cognate antigen. These results lead us to postulate that antinucleosome autoantibodies could have different origins. Since both anti-DNA and anti-nucleosome autoantibodies are produced during the course of systemic lupus erythematosus, a non-organ specific autoimmune disease, a comparative structural and electrostatic analysis of the two populations of autoantibodies may constitute a way to elucidate their origin and the role of the antigen in tolerance breakdown. The present study illustrates some interests, advantages and limits of a methodology based on the use of comparative modeling and analysis of molecular surface properties.
通过分析六种抗核小体自身抗体可变片段，证明了比较分子建模在阐明结构-功能关系方面的价值。使用COMPOSER软件中开发的自动化程序构建结构模型，随后用AMBER力场进行最小化，并根据若干标准几何和化学标准进行验证。Chothia和Lesk的研究成果[Chothia和Lesk，《分子生物学杂志》，196 (1987) 901；Chothia等人，《自然》，342 (1989) 877]中的典型类别分配被用作六个高变环中五个的补充验证工具。基于抗原结合可能通过静电相互作用发生的假设进行的分析，揭示了抗核小体或抗组蛋白抗体与其同源抗原可能的多种结合机制。这些结果使我们推测抗核小体自身抗体可能有不同的起源。由于抗DNA和抗核小体自身抗体都是在系统性红斑狼疮（一种非器官特异性自身免疫性疾病）过程中产生的，对这两种自身抗体群体进行比较结构和静电分析可能是阐明它们的起源以及抗原在耐受性破坏中的作用的一种方法。本研究说明了基于比较建模和分子表面性质分析的方法的一些优点、优势和局限性。
