Theory and Modeling of Noncovalent Binding

非共价结合的理论和建模

• 批准号: 7887055
• 负责人: MICHAEL K. GILSON
• 金额: $ 37.49万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7887055
• 关键词: Affinity; Binding; Binding Proteins; Binding Sites; Biology; Biophysics; Case Study; Catalysis; Chemicals; Computer Simulation; Computer software; Development; Drug or Chemical; Engineering; Entropy; Enzymes; Equation; Equilibrium; Evaluation; FDA approved; Free Energy; Generations; Goals; Grant; Guidelines; Immune system; Ligand Binding; Ligands; Mechanical Stress; Medical; Medicine; Metabolism; Methods; Modeling; Molecular; Molecular Conformation; Motion; Mutation; Pattern; Pharmaceutical Preparations; Physics; Process; Protein Binding; Protein Engineering; Proteins; RGD (sequence); Regulation; Research; Research Personnel; Scientist; Shapes; Signal Transduction; Site; Solvents; Speed; Stress; Structure; System; Testing; Therapeutic; Time; Work; biological systems; design; engineering design; improved; insight; molecular recognition; public health relevance; receptor; receptor binding; simulation; small molecule; software development; theories; tool

DESCRIPTION (provided by applicant): The proposed research, which is purely theoretical and computational, has three main parts, all focused on aspects of the phenomenon of molecular recognition, which is of basic and practical importance in biology and medicine. The first part concerns miniature receptor molecules, called hosts, which are used today to stabilize and deliver many drugs and which also show promise as medications in their own right. We plan to provide other scientists with new, tested software to help them design these miniature receptors and thereby speed the development of new medications. We also plan to carry out simulations of these molecules in order to develop a better understanding of how they work and also to gain insight into how larger receptors, such as many proteins, bind drugs. The second part is to study the changes in entropy that occur when molecules bind. In recent work, we have found that changes in entropy associated with the motions of receptors and the molecules they bind (ligands) can have a surprisingly strong influence on how tightly they bind each other. However, we do not yet understand these entropy changes well enough to make them work in our favor when designing tight-binding receptors and ligands. We plan to further develop our method of computing these entropy changes from computer simulations, and then use the method to develop a better understanding of them. For example, we would like to be able to predict when modifying a ligand to make it more rigid, and therefore lower in entropy, will increase its affinity. In addition, we plan to incorporate the new entropy calculations into software for computing binding affinities which we hope will help researchers design new drugs. The third part is to develop a new idea of applying the concept of stress to molecular biophysics. Materials scientists have come up with equations for computing the stress in a material from an atomistic computer simulation, and we think these equations can tell us something useful about how hosts, proteins and other molecules work. For one thing, we hypothesize that if receptor- ligand binding produces localized stress, then modifying the ligand to reduce this stress might increase the binding affinity. Thus, computing stress might help with the design of tight-binding ligands. We also hypothesize that, when a ligand binds an allosteric protein, a protein whose conformation shifts on binding, the mechanism of the shape change involves propagation of a wave of stress from the binding site. If we can understand how proteins change conformation, this would help us to re-engineer them for medical and industrial uses. PUBLIC HEALTH RELEVANCE: This project applies chemical theory and computer modeling to the phenomenon of molecular recognition. Our overall goal is to develop a better understanding of what makes specific molecules bind each other, and to incorporate this understanding into software that will be useful in protein engineering and the design of new medications.

描述（由申请人提供）：拟议的研究纯粹是理论和计算，具有三个主要部分，都集中在分子识别现象的各个方面，这在生物学和医学中至关重要。第一部分涉及称为宿主的微型受体分子，这些分子今天用于稳定和输送许多药物，并且本身也表现出有望作为药物。我们计划为其他科学家提供新的，经过测试的软件，以帮助他们设计这些微型受体，从而加快新药物的开发。我们还计划对这些分子进行模拟，以便更好地了解它们的工作方式，并深入了解更大的受体（例如许多蛋白质）如何结合药物。第二部分是研究分子结合时发生的熵变化。在最近的工作中，我们发现与受体运动和结合的分子（配体）相关的熵变化可能会对它们彼此的紧密结合程度产生令人惊讶的强烈影响。但是，我们尚不理解这些熵的变化足以使它们在设计紧密结合的受体和配体时对我们有利。我们计划进一步开发计算计算机模拟的这些熵变化的方法，然后使用该方法对它们进行更好的了解。例如，我们希望能够预测在修改配体以使其更加刚性，因此熵较低的情况会增加其亲和力。此外，我们计划将新的熵计算纳入计算结合亲和力的软件中，我们希望这将帮助研究人员设计新药。第三部分是开发一种将压力概念应用于分子生物物理学的新想法。材料科学家提出了计算原子计算机模拟材料中应力的方程式，我们认为这些方程式可以告诉我们一些关于宿主，蛋白质和其他分子如何工作的有用的东西。一方面，我们假设如果受体结合产生局部应力，那么修改配体以减少这种应力可能会增加结合亲和力。因此，计算应力可能有助于设计紧密结合配体的设计。我们还假设，当配体结合变构蛋白时，一种蛋白质的构素会在结合上转移时，形状变化的机理涉及从结合位点传播应力波。如果我们能够理解蛋白质如何改变构象，这将有助于我们重新设计其用于医疗和工业用途。 公共卫生相关性：该项目将化学理论和计算机建模应用于分子识别现象。我们的总体目标是更好地了解使特定分子相互结合的原因，并将这种理解纳入将在蛋白质工程和新药物设计中有用的软件中。