Thermodynamic mechanism for the evasion of antibody neutralization in flaviviruses.
Thermodynamic mechanism for the evasion of antibody neutralization in flaviviruses.
复制标题
DOI：
10.1021/ja503318x
复制
发表时间：
2014-07-23
影响因子：
15
通讯作者：
Lee, J. Ching
中科院分区：
文献类型：
--
作者：
Maillard, Rodrigo A.;Liu, Tong;Beasley, David W. C.;Barrett, Alan D. T.;Hilser, Vincent J.;Lee, J. Ching
抗原蛋白表位的突变可以赋予病毒对抗体介导的中和作用的抗性。然而，表征表位残基的基本特性以及突变如何影响抗体结合以改变病毒对中和的敏感性仍然很大程度上未知。为了解决这些问题，我们使用基于集成的算法来表征突变对蛋白质构象波动热力学的影响。我们将此方法应用于两种医学上重要的黄病毒（西尼罗河病毒和登革热 2 号）的包膜蛋白结构域 III (ED3)。我们确定了残基对热力学扰动的敏感性与表位位置之间的密切关系。尽管序列和结构高度相似，但这种关系使得能够成功鉴定每个 ED3 中的主要表位。允许 ED3 逃避抗体检测的突变会通过局部效应或长程相互作用增加或减少表位的构象波动。空间上遥远的相互作用起源于 ED3 整体构象的重新分布，而不是通过机械连接的连续氨基酸阵列。这些结果与之前关于通过远离表位的突变逃避中和的观察结果相一致。最后，我们建立了表位构象波动的细微变化与抗体结合亲和力的大缺陷之间的定量相关性。这种相关性表明，允许病毒生长的突变在减少中和作用的同时，不会产生显着的结构变化，并强调了蛋白质波动和长程相互作用在抗体介导的中和抵抗机制中的重要性。
Mutations in the epitopes of antigenic proteins can confer viral resistance to antibody-mediated neutralization. However, the fundamental properties that characterize epitope residues and how mutations affect antibody binding to alter virus susceptibility to neutralization remain largely unknown. To address these questions, we used an ensemble-based algorithm to characterize the effects of mutations on the thermodynamics of protein conformational fluctuations. We applied this method to the envelope protein domain III (ED3) of two medically important flaviviruses: West Nile and dengue 2. We determined an intimate relationship between the susceptibility of a residue to thermodynamic perturbations and epitope location. This relationship allows the successful identification of the primary epitopes in each ED3, despite their high sequence and structural similarity. Mutations that allow the ED3 to evade detection by the antibody either increase or decrease conformational fluctuations of the epitopes through local effects or long-range interactions. Spatially distant interactions originate in the redistribution of conformations of the ED3 ensembles, not through a mechanically connected array of contiguous amino acids. These results reconcile previous observations of evasion of neutralization by mutations at a distance from the epitopes. Finally, we established a quantitative correlation between subtle changes in the conformational fluctuations of the epitope and large defects in antibody binding affinity. This correlation suggests that mutations that allow viral growth, while reducing neutralization, do not generate significant structural changes and underscores the importance of protein fluctuations and long-range interactions in the mechanism of antibody-mediated neutralization resistance.
登录
查看更多内容
影响因子：
3.7
作者：
Hiramatsu, K;Tadano, M;Lai, CJ
通讯作者：
Lai, CJ
影响因子：
3.8
作者：
CECILIA, D;GADKARI, DA;GHOSH, SN
通讯作者：
GHOSH, SN
DOI：
10.1073/pnas.95.17.9903
发表时间：
1998-08-18
影响因子：
11.1
作者：
Hilser, VJ;Dowdy, D;Freire, E
通讯作者：
Freire, E
影响因子：
3.7
作者：
Gromowski, Gregory D.;Roehrig, John T.;Barrett, Alan D. T.
通讯作者：
Barrett, Alan D. T.
DOI：
10.4049/jimmunol.1200227
发表时间：
2012-05-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Midgley CM;Flanagan A;Tran HB;Dejnirattisai W;Chawansuntati K;Jumnainsong A;Wongwiwat W;Duangchinda T;Mongkolsapaya J;Grimes JM;Screaton GR
通讯作者：
Screaton GR