CAREER: Computational Characterization of Protein Hydration and Interactions

职业：蛋白质水合和相互作用的计算表征

• 批准号: 1652646
• 负责人: Amish Patel
• 金额: $ 50万
• 依托单位: University of Pennsylvania
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1652646&HistoricalAwards=false
• 关键词: CAREER; Computational; Characterization; Protein; Hydration

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.

主要研究者：Patel，Amish J.Proposal Number：1652646机构：宾夕法尼亚大学标题：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 binding partners.因此，蛋白质-水相互作用在蛋白质水合、其稳定性以及其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-水相互作用是具有挑战性的，因为它们不仅取决于化学，而且还取决于蛋白质表面呈现的精确形貌和化学模式。因此，缺乏对水结构如何在蛋白质界面扰动以及这种扰动如何反过来影响蛋白质相互作用的基本理解。 该提案的目标是描述和了解蛋白质表面及其水合沃茨之间的相互作用，并向从小学到研究生的学生，特别是来自弱势背景的学生，介绍蛋白质水合和相互作用的各个方面。通过使用创新的教学方法和材料。该项目的结果将广泛传播给研究界和公众。为了全面表征蛋白质-水相互作用，PI将采用新的模拟技术，对整个蛋白质水化壳层中的水分子施加不利的偏置电位。随着电位强度的增加，蛋白质-水相互作用被系统地破坏，并且水合壳沃茨对所施加的电位的响应包含丰富的信息，可以分析这些信息以：（1）确定与水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水合不同配体形状空腔的自由能，其告知蛋白质-配体相互作用，和（3）鉴定蛋白质上的超亲水性补丁，其允许它们与水具有强相互作用，并询问这种相互作用是否能够在脱水时稳定蛋白质。拟议的研究有望通过提供分子水平的理解和揭示其对蛋白质相互作用和组装的影响来开辟新的领域。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令人兴奋的前沿。

项目成果

Protein Hydration Waters Are Susceptible to Unfavorable Perturbations

• DOI: 10.1021/jacs.8b11448
• 发表时间: 2019-02-06
• 期刊: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
• 影响因子: 15
• 作者: Rego, Nicholas B.;Xi, Erte;Patel, Amish J.
• 通讯作者: Patel, Amish J.

Protein Hydration Thermodynamics: The Influence of Flexibility and Salt on Hydrophobin II Hydration

蛋白质水合热力学：柔韧性和盐对疏水蛋白 II 水合的影响

• DOI: 10.1021/acs.jpcb.7b12060
• 发表时间: 2017
• 期刊: The Journal of Physical Chemistry B
• 作者: Remsing, Richard C.;Xi, Erte;Patel, Amish J.
• 通讯作者: Patel, Amish J.

Sparse sampling of water density fluctuations near liquid-vapor coexistence

液汽共存附近水密度波动的稀疏采样

• DOI: 10.1080/08927022.2018.1457218
• 发表时间: 2017
• 期刊: Molecular Simulation
• 影响因子: 2.1
• 作者: Xi, Erte;Marks, Sean M.;Fialoke, Suruchi;Patel, Amish J.
• 通讯作者: Patel, Amish J.

Characterizing the Interplay between Polymer Solvation and Conformation

• DOI: 10.1021/acs.jpcb.1c02191
• 发表时间: 2021-05-12
• 期刊: JOURNAL OF PHYSICAL CHEMISTRY B
• 影响因子: 3.3
• 作者: Dhabal, Debdas;Jiang, Zhitong;Patel, Amish J.
• 通讯作者: Patel, Amish J.

Hydrophobicity of proteins and nanostructured solutes is governed by topographical and chemical context

• DOI: 10.1073/pnas.1700092114
• 发表时间: 2017-11
• 期刊: Proceedings of the National Academy of Sciences
• 作者: E. Xi;V. Venkateshwaran;Lijuan Li;Nicholas B Rego;Amish J. Patel;S. Garde