蛋白质-连接体结合中的合规和溶解之间的相互作用
Maria Luisa Verteramo1, Olof Stenström2, Majda Misini Ignjatović3
1Centre for Analysis and Synthesis, Department of Chemistry , Lund University , 221 00 Lund , Sweden.
Journal of the American Chemical Society
|January 9, 2019
概括
了解分子识别需要解剖结合热力学. 这项研究揭示了形态,而不是溶解,主导着对galectin-3的配体结合 afinity 的差异,为药物设计提供了洞察力.
科学领域:
- 生物化学和分子生物学
- 化学热力学
- 结构生物学
背景情况:
- 分子识别在化学和生物学中至关重要,但解剖结合热力学,特别是贡献,仍然具有挑战性.
- 这些相互作用的关键目标是 Galectin-3 的碳水化合物识别域.
- 准确评估性贡献对于解释分子层面的结合事件至关重要.
研究的目的:
- 阐明在加勒-3碳水化合物识别领域中对联体亲和力差异的分子决定因素
- 量化评估和对结合自由能量的贡献.
- 在蛋白质 - 连接体相互作用中区分构造和溶解的作用.
主要方法:
- 用于结合热力学的异热定位热量计 (ITC).
- 进行X射线结晶学以确定结构.
- 用于形状动态的NMR放松和分子动力学 (MD) 模拟.
- 电网不均质溶解理论 (GIST) 用于溶解自由能分析.
主要成果:
- 使用具有相似未结合的化学潜力的二聚体配体来分离结合差异.
- 和表现出补偿性行为, ΔΔH°(R - S) = -5 ± 1 kJ/mol和 -TΔΔS°(R - S) = 3 ± 1 kJ/mol.
- S-立体同位素复合体表现出比R-立体同位素复合体更大的蛋白质构成.
- GIST的计算表明S复合体的溶解贡献较小,较为有利.
结论:
- 在区分对甲基-3 的联结亲和力方面,形态对溶解起着主导作用.
- 在合理的药物设计中,形态和溶解之间的相互作用既带来了机遇,也带来了挑战.
- 这项研究为结合热力学提供了详细的分子理解.
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