Theoretical Studies of Protein-Ligand Binding Energetics and Kinetics

9808202夏普这项研究旨在了解蛋白质与其配体特定结合的物理和化学基础。目标是回答在蛋白质的生物功能中起重要作用的两个关键问题：i)蛋白质和配体的结构和化学性质如何导致正确的结合络合物具有良好的能量学(高亲和力)？II)结构和化学性质如何控制外力作用下的离解动力学。结合分子力学和有限差分Poisson-Boltzmann方法计算结合自由能。根据分子动力学模拟得到的结构的波动，计算复合体中的内部平移和旋转熵的变化。布朗动力学将用于研究蛋白质-配体体系在内力和外力作用下的解离动力学。影响解离的溶剂筛选作用力将使用有限差分Poisson-Boltzmann方法包括在内。布朗动力学模拟将被用来理解蛋白质-配体相互作用的结构和解离动力学之间的关系，这些相互作用确实或不介导细胞黏附。计算并最终预测一种蛋白质与其他分子(配体)结合的紧密程度的能力可称为“结合亲和力问题”，它与现代结构生物学中的其他主要问题如“蛋白质折叠问题”和蛋白质催化活性的基础并列重要。了解蛋白质的结构如何使其与特定的靶分子结合，将在分子水平上增加我们对许多生物事件的了解，如抗体-抗原亲和力、抗原性、信号转导途径的特异性、抑制剂的功能等。结合问题的研究应用还包括蛋白质工程。了解蛋白质在外力作用下脱离配体的机制和速率，对于理解细胞所表现出的不同黏附行为是很重要的。模拟解离动力学的能力将有助于阐明分子结构、解离与细胞黏附等重要生物学功能之间的关系。

9808202 Sharp This research is directed at understanding the physical and chemical basis of specific binding of proteins to their ligands. The goal is to answer two key questions that play an important part in the biological function of proteins: i) How do the structure and chemical properties of the protein and ligand result in favorable energetics (high affinity) for the correct binding complex? ii) How do the structure and chemical properties control the dissociation kinetics under applied forces. The binding free energy will be calculated using a combination of molecular mechanics and finite difference Poisson-Boltzmann methods. Changes in internal translation and ratational entropy in the complex will be computed from fluctuations in the structure obtained from molecular dynamics simulations. Brownian dynamics will be used to study the dissociation kinetics of protein-ligand systems in the presence of intrinsic and extrinsic (mechanical) forces. Solvent screened forces that affect the dissociation will be included using a finite difference Poisson-Boltzmann approach. Brownian dynamics simulations will be used to understand the relationship between structure and dissociation kinetics of protein-ligand interactions that do or do not mediate cell adhesion. The ability to calculate and eventually predict how tightly a protein binds other molecules (ligand) may be termed the "binding affinity problem", and it ranks in importance with other major problems in modern structural biology such as the "protein folding problem", and the basis of catalytic activity in proteins. The ability to understand how the structure of a protein enables it to bind a specific target molecule will increase our understanding of many biological events at the molecular level such as antibody-antigen-affinity, antigenicity, specificity in signal transduction pathways, the function of inhibitors, etc. Applications of research on the binding problem also include protein engineering. Understanding the mechanism an d rate at which proteins become unbound from their ligands in the presence of forces is important in understanding the different adhesion behaviors shown by cells. The ability to simulate dissociation kinetics will shed light on the relationship between molecular structure, dissociation and biologically important functions such as cell adhesion.