In Silico Design of High-Affinity gp100 Antigenic Mimotopes for Targeting Melanoma.

IF 2.9 2区 化学 Q3 CHEMISTRY, PHYSICAL
The Journal of Physical Chemistry B Pub Date : 2025-07-31 Epub Date: 2025-07-22 DOI:10.1021/acs.jpcb.5c01507
Rui Ye, Yuxuan Yang, Kevin C Chan, Dong Zhang, Ruhong Zhou
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引用次数: 0

Abstract

Human CD8+ cytotoxic T lymphocytes (CTLs) induce melanoma regression by utilizing T-cell receptors (TCRs) to recognize tumor-specific epitopes. One such epitope, gp100280-288(288 V) (YLEPGPVTV), is presented by human leukocyte antigen (HLA)-A*02:01 molecules. Computational approaches, particularly the predictions on peptide-HLA (pHLA) and TCR-pHLA binding affinities, are complementary to experimental approaches in guiding further optimization and design of the gp100280-288(288 V) peptide (mimotopes) for enhanced antitumor responses. Here, with all-atom molecular dynamics (MD) simulations and free energy perturbation (FEP) methods, we designed a series of potential mimotopes through in silico mutagenesis studies of gp100280-288(288 V) utilizing the latest affinity-matured TCR structure. Our results showed that E3I and E3L mutants increased HLA binding without affecting TCR binding, indicating their potential as epitope candidates. Conversely, the E3A and E3V mutations improved peptide-HLA binding but weakened the TCR-pHLA binding affinity. In-depth structural analysis revealed that insufficient occupancy of the HLA pocket by residue 3 in the E3A and E3V mutants would induce a twisted peptide conformation at positions 4 to 6, disrupting the interaction between TCR and pHLA. Therefore, it is crucial to consider the impact of single-residue mutations that alter peptide conformation on TCR binding when designing effective antigenic mimotopes. Furthermore, the E3I+V7L and E3L+V7L double mutants are also found to produce favorable binding affinity changes similar to those of the E3I and E3L mutants, suggesting their potential as advantageous mimotope candidates. Our work provides structural insights for the rational design of favorable gp100 mimotopes and may contribute to developing gp100 epitope-based vaccines.

针对黑色素瘤的高亲和力gp100抗原模位的芯片设计。
人类CD8+细胞毒性T淋巴细胞(ctl)通过利用T细胞受体(tcr)识别肿瘤特异性表位诱导黑色素瘤消退。其中一个表位gp100280-288(288 V) (YLEPGPVTV)是由人白细胞抗原(HLA)-A*02:01分子呈递的。计算方法,特别是对肽- hla (pHLA)和TCR-pHLA结合亲和力的预测,是指导进一步优化和设计gp100280-288(288 V)肽(模位)以增强抗肿瘤反应的实验方法的补充。本文采用全原子分子动力学(MD)模拟和自由能摄动(FEP)方法,利用最新的亲和成熟的TCR结构,对gp100280-288(288 V)进行了硅诱变研究,设计了一系列潜在的mimotopes。我们的研究结果表明,E3I和E3L突变体增加了HLA结合而不影响TCR结合,这表明它们有可能成为表位候选者。相反,E3A和E3V突变改善了肽- hla结合,但削弱了TCR-pHLA结合亲和力。深入的结构分析表明,在E3A和E3V突变体中,残基3对HLA囊的占用不足会导致4至6位的扭曲肽构象,破坏TCR和pHLA之间的相互作用。因此,在设计有效的抗原模位时,考虑改变肽构象的单残基突变对TCR结合的影响是至关重要的。此外,E3I+V7L和E3L+V7L双突变体也被发现产生类似于E3I和E3L突变体的有利结合亲和力变化,这表明它们有潜力成为有利的模位候选者。我们的工作为合理设计有利的gp100表位提供了结构见解,并可能有助于开发基于gp100表位的疫苗。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
5.80
自引率
9.10%
发文量
965
审稿时长
1.6 months
期刊介绍: An essential criterion for acceptance of research articles in the journal is that they provide new physical insight. Please refer to the New Physical Insights virtual issue on what constitutes new physical insight. Manuscripts that are essentially reporting data or applications of data are, in general, not suitable for publication in JPC B.
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