THEORETICAL STUDIES OF PROTEIN LIGAND INTERACTIONS

热力学模拟方法现在可以提供详细的原子水平 蛋白质和蛋白质的结构-热力学关系信息 溶液中的生物聚合物。继续发展和应用 这些新方法将在拟议的研究中讨论。这些 技术，以及计算自由能、能量和 信息论将应用于生物物理学的三个基本领域的研究： (I)酶-抑制剂相互作用中的构象影响 热力学；(2)蛋白质稳定性的变化 位点突变；(Iii)折叠的热力学稳定性和动力学 水和非水中的次生和超次生结构 环境。二氢叶酸还原酶、NADPH和NADPH三元络合物 甲氧苄氨嘧啶的同系物将作为详细的 蛋白质和蛋白质存在时相互作用热力学研究 抑制物构象灵活性。从这些研究中概括出来 方法将先进并直接与核磁共振测量进行比较 将会产生配基动力学。其次，我们要研究的是 噬菌体T4溶菌酶(Tr-157)突变体的检测 突变时的结构和热力学稳定性。原子水平基础 因为这些变化将通过热力学组件的应用来寻求 分析和蛋白质动力学。最后，我们将探索潜在的 蛋白质和多肽的结构稳定性原理。组合在一起 将使用约束动力学和热力学模拟方法来 计算形成的自由能、能量和熵面 极地和非极地环境中的折叠图案。 所描述的研究的性能将提供新的和扩展的 热力学性质计算中使用的方法。它 也将促进我们对基本原则的理解 主导酶-抑制物结合、蛋白质稳定性和继发性 结构的形成和稳定性。

Thermodynamic simulation methods can now provide detailed atomic level information on structure-thermodynamic relationships for proteins and biopolymers in solution. The continued development and application of these new methods will be addressed in the proposed studies. These techniques, together with methods to compute free energies, energies and entropies will be applied to study three fundamental areas of biophysics: (i) conformational influences in enzyme-inhibitor interaction thermodynamics; (ii) changes in protein stability on the introduction of site mutations; (iii) thermodynamic stability and kinetics of folding for secondary and supersecondary structures in aqueous and non-aqueous environments. Ternary complexes of dihydrofolate reductase, NADPH and congeners of trimethoprim will serve as a prototype system for detailed investigations of interaction thermodynamics in the presence of protein and inhibitor conformational flexibility. From these studies general methodology will be advanced and direct comparison with NMR measurements of ligand dynamics will be made. Secondly, we will study the system of mutants from bacteriophage T4 lysozyme (thr-157) to examine changes in structure and thermodynamic stability upon mutation. An atomic level basis for these changes will be sought by application of thermodynamic component analysis and protein dynamics. Finally, we will explore the underlying principles of structural stability of protein and peptides. Combined constrained dynamics and thermodynamic simulation methods will be used to calculate free energy, energy and entropy surfaces for the formation of folded motifs in polar and apolar environments. The performance of the research described will provide new and extended methodologies for use in the calculation of thermodynamic properties. It will also bring about advances in our understanding of the basic principles governing enzyme-inhibitor association, protein stability and secondary structure formation and stability.