Packing and Electrostatic Effects on Folding and Binding

这项工作的广泛的长期目标是发展和应用理论模型 分析和设计蛋白质折叠过程中形成的互补相互作用， 约束力分子以适当的亲和力相互识别的能力， 特异性是生物学和医学的核心。药物的临床活性 代理人是由于他们的能力，识别和干扰一个或一小部分 分子靶点;不良副作用经常由缺乏特异性引起 对预定目标。一个重要的研究领域涉及了解设计 天然蛋白质分子的原理和开发工具， 一种全新的分子。目前的建议侧重于（1）进一步 分子结构的研究和工程方法的发展， 结合配偶体和（2）对感兴趣的特定生物分子的应用。 所追求的方法改进将包括提高设计的稳健性 通过减少误报率，改善平衡， 包装和静电相互作用，以及更有效的处理技术， 构象松弛这些新方法将应用于 用于结构和细胞生物学以及计算抗体成熟的新试剂。

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.