Packing and Electrostatic Effects on Folding and Binding

这项工作的长期目标是开发和应用理论模型。 分析和设计蛋白质折叠过程中形成的互补相互作用 有约束力的。分子以适当的亲和力识别彼此的能力 专一性是生物学和医学的核心。药物的临床活性 代理在很大程度上是由于他们识别和干扰一个或少数代理的能力 指分子靶标；不良副作用通常是由于缺乏特异性而引起的 对于预定的目标。研究的一个重要领域涉及理解设计 天然蛋白质分子的原理和改造或改造的开发工具 通过类似原理的全新分子。目前的建议侧重于(1)进一步 分子结构和工程研究的方法学进展 结合伙伴和(2)对特定的感兴趣生物分子的应用。 所追求的方法改进将包括改进设计的健壮性 通过降低假阳性率、改善平衡来实现方法 包装和静电相互作用，以及更有效的治疗技术 构象弛豫。这些新方法将被应用于设计和研究。 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.