Packing and Electrostatic Effects on Folding and Binding

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。分子以适当的亲和力和特异性相互识别的能力是生物学和医学的核心。药物的临床活性在很大程度上是由于它们识别和干扰一个或少数分子靶点的能力；不良副作用往往是由于缺乏预期靶点的特异性而引起的。研究的一个重要领域包括了解天然蛋白质分子的设计原理，并开发工具以利用类似原理设计修饰或全新的分子。目前的建议侧重于(1)进一步发展分子结构和结合伙伴的研究和工程方法，以及(2)将其应用于感兴趣的特定生物分子。所追求的方法学改进将包括通过降低假阳性率来提高设计方法的稳健性，改善堆积和静电相互作用的平衡，以及更有效地处理构象松弛的技术。这些新方法将被应用于结构和细胞生物学新试剂的设计和研究，以及计算抗体成熟。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相结合的方式开发出来的。本文所进行的研究将改进计算设计方法。由此产生的技术可能会导致新药更快的开发和更好的疗效。

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.