Packing and Electrostatic Effects on Folding and Binding

包装和静电对折叠和装订的影响

• 批准号: 7579654
• 负责人: BRUCE TIDOR
• 金额: $ 25.19万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7579654
• 关键词: Adverse effects; Affinity; Algorithms; Antibodies; Antibody Affinity; Area; Avastin; Binding; Biological; Biology; Biotin; Cellular biology; Charge; Clinical; Collaborations; Development; Electrostatics; Engineering; Equilibrium; Feedback; Goals; Investigation; Label; Lanthanoid Series Elements; Lead; Life; Magnetism; Medicine; Methodology; Methods; Metric; Molecular; Molecular Models; Molecular Structure; Molecular Target; Pharmacologic Substance; Pharmacotherapy; Property; Protein Binding; Protein Binding Domain; Proteins; Reagent; Relaxation; Research; Research Design; Roentgen Rays; Specificity; Streptavidin; Structure; System; Techniques; Technology; Testing; Theoretical model; Therapeutic; Therapeutic antibodies; Variant; Work; antiangiogenesis therapy; base; biological systems; design; improved; interest; luminescence; molecular modeling; novel; protein complex; protein folding; protein structure; public health relevance; research study; therapeutic angiogenesis; tool; usability

DESCRIPTION (provided by applicant): The broad long-term objectives of this work are to develop and apply theoretical models to analyze and to design complementary interactions formed during protein folding and binding. The ability of molecules to recognize one another with appropriate affinity and specificity is central to biology and medicine. The clinical activity of pharmaceutical agents is due largely to their ability to recognize and interfere with one or a small number of molecular targets; undesirable side effects are frequently caused by lack of specificity for the intended target. An important area of research involves understanding the design principles of natural protein molecules and developing tools to engineer modified or entirely new molecules by similar principles. The current proposal focuses on (1) further developments in methodology for the study and engineering of molecular structures and binding partners and (2) applications to particular biological molecules of interest. Methodological enhancements pursued will include improving the robustness of design approaches through a reduction in the rate of false positives, improvement in the balance of packing and electrostatic interactions, and more efficient techniques for treating conformational relaxation. The new methods will be applied to the design and study of novel reagents for structural and cell biology and to computational antibody maturation. PUBLIC HEALTH RELEVANCE: Modern drug therapies are developed through a combination of experimental study and computational design. The research pursued here will improve computational design approaches. The resulting techniques could lead to more rapid development and improved efficacy of new medicines.

描述（由申请人提供）：这项工作的广泛长期目标是开发和应用理论模型来分析和设计蛋白质折叠和结合过程中形成的互补相互作用。分子具有适当亲和力和特异性彼此识别的能力对于生物学和医学至关重要。药物的临床活性主要是由于它们识别和干扰一个或少数分子靶标的能力。不良的副作用通常是由于预期目标缺乏特异性而引起的。研究的重要领域是了解天然蛋白质分子的设计原理以及开发工具以通过类似原则来改造或全新的分子来设计工具。当前的提案重点是（1）分子结构和结合伙伴的研究和工程方法的进一步发展，以及（2）对特定感兴趣的生物分子的应用。追求的方法学增强功能将包括通过降低误报率，改善包装和静电相互作用的改善以及更有效的治疗构象放松的技术来提高设计方法的鲁棒性。新方法将应用于用于结构和细胞生物学的新试剂以及计算抗体成熟的设计和研究。公共卫生相关性：现代药物疗法是通过实验研究和计算设计的结合而开发的。这里进行的研究将改善计算设计方法。由此产生的技术可能会导致更快的发展和改善新药物的功效。