CAREER: Computational Characterization of Protein Hydration and Interactions

PI：Patel，Amish J.Proposal Number：1652646机构：宾夕法尼亚大学标题：Career：蛋白质水化和相互作用的计算特征因为所有生物学都发生在水中，每个生物分子结合过程都涉及蛋白质-水相互作用被破坏，并被结合伙伴之间的直接相互作用所取代。因此，蛋白质-水的相互作用在蛋白质的水合作用、稳定性以及与配体和其他蛋白质的相互作用中起着至关重要的作用。然而，表征蛋白质-水的相互作用是具有挑战性的，因为它们不仅取决于化学，而且取决于蛋白质表面呈现的精确地形和化学模式。因此，对蛋白质界面的水结构是如何扰动的，以及这种扰动是如何影响蛋白质相互作用的，缺乏基本的了解。这项建议的目的是描述和了解蛋白质表面与其水合水之间的相互作用，并通过使用创新的教学方法和材料向从小学到研究生的学生，特别是来自贫困背景的学生介绍蛋白质水合和相互作用的各个方面。这个项目的结果将广泛传播给研究界和公众。为了能够全面表征蛋白质与水的相互作用，PI将使用新的模拟技术对整个蛋白质水合壳中的水分子施加不利的偏置电势。随着势的强度增加，蛋白质-水相互作用被系统地破坏，并且水化壳水对所施加的势的响应包含丰富的信息，这些信息可被分析以：(1)识别与水的相互作用最弱的蛋白质区域，并研究它们是否可以作为蛋白质相互作用界面的预测因子，(2)估计蛋白质水化壳中各种配体形状的空腔的水化自由能，其告知蛋白质-配体相互作用，以及(3)识别蛋白质上允许它们与水具有强相互作用的超亲水斑块，并询问这种相互作用是否能够在脱水时稳定蛋白质。这项拟议的研究承诺通过提供分子水平的理解并揭示其对蛋白质相互作用和组装的影响而开辟新的天地。随着新的蛋白质结构继续以令人难以置信的速度被解决，调节蛋白质相互作用有望成为寻找新疗法的一个令人兴奋的前沿。

PI: Patel, Amish J.Proposal Number: 1652646 Institution: University of Pennsylvania Title: CAREER: Computational Characterization of Protein Hydration and InteractionsBecause all of biology happens in water, every biomolecular binding process involves protein-water interactions being disrupted, and replaced by direct interactions between the binding partners. Protein-water interactions thus play a crucial role in protein hydration, its stability, as well as its interactions with ligands and other proteins. However, characterizing protein-water interactions is challenging, because they depend not only on the chemistry, but also on the precise topography and the chemical pattern presented by the protein surface. As a result, a fundamental understanding of how water structure is perturbed at protein interfaces, and how this perturbation in turn affects protein interactions, is lacking. The goal of this proposal is to characterize and understand the interactions between protein surfaces and their hydration waters, and to introduce students ranging from elementary to graduate school, especially those from disadvantaged backgrounds, to aspects of protein hydration and interactions through the use of innovative teaching methods and materials. The results from this project will be broadly disseminated to the research community and the general public.To enable a comprehensive characterization of protein-water interactions, the PI will employ novel simulation techniques to apply an unfavorable biasing potential to water molecules in the entire protein hydration shell. As the strength of the potential is increased, protein-water interactions are systematically disrupted, and the response of the hydration shell waters to the applied potential contains a wealth of information that can be analyzed to: (1) identify regions of the protein that have the weakest interactions with water, and investigate whether they can serve as predictors of protein interaction interfaces, (2) estimate free energies for hydrating diverse ligand-shaped cavities in the protein hydration shell, which inform protein-ligand interactions, and (3) identify super-hydrophilic patches on the protein that allow them to have strong interactions with water, and interrogate whether such interactions are able to stabilize the protein upon dehydration. The proposed research promises to break new ground by providing molecular level understanding and uncovering its impact on protein interactions and assembly. As novel protein structures continue to be solved at an incredible rate, modulating protein interactions promises to be an exciting frontier in the search for novel therapeutics.