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 关于蛋白质结构-热力学关系的信息， 生物聚合物溶液。 继续发展和应用 这些新方法将在拟议的研究中加以讨论。 这些 技术，以及计算自由能，能量和 熵将应用于研究生物物理学的三个基本领域： (i)构象对酶-抑制剂相互作用的影响 热力学;（ii）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， 水溶液和非水溶液中的二级和超二级结构 环境. 二氢叶酸还原酶、NADPH和 甲氧苄啶的同系物将作为详细的原型系统， 研究了蛋白质和 抑制剂构象柔性。 根据这些研究， 方法将是先进的，直接比较与核磁共振测量的 将进行配体动力学。 其次，我们将研究 噬菌体T4溶菌酶（thr-157）的突变体，以检查 结构和突变时热力学稳定性。 原子水平的基础 对于这些变化，将通过应用热力学分量来寻求 分析和蛋白质动力学。 最后，我们将探讨潜在的 蛋白质和肽的结构稳定性原理。 组合 约束动力学和热力学模拟方法将用于 计算自由能，能量和熵表面的形成 在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 用于计算热力学性质的方法。 它 也将促进我们对基本原则的理解 控制酶-抑制剂缔合、蛋白质稳定性和次级 结构形成和稳定性。

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.