COMPUTER SIMULATION OF HEMOGLOBIN ELECTROSTATICS

计算机模拟将用于研究结构/功能 人类血红蛋白的关系。 计算将利用 估计自由能变化的现代模拟方法，以及 一些静电相互作用的连续描述，研究 血红蛋白与质子和阴离子的相互作用， 四聚体解离成二聚体，结构力 随后配体结合到T四级状态。 这些详细 由于计算能力的最新发展， 在模拟算法中，并通过相应的高- 突变体和部分配体的分辨率X射线衍射研究 血红蛋白 这些进展，加上收集到的大量证据 在过去的十年中，对突变血红蛋白的特性进行了研究， 可能有各种各样的测试来测试我们理解亚单位的能力 原子水平上的缔合和变构相互作用的细节。 要研究的具体相互作用包括：（a）质子和 （B）四聚体/二聚体的能量学 正常和突变血红蛋白的解离;（c）结构和 将配体结合到T状态结构的能量后果;以及（d） 在血红蛋白Ypsilanti中观察到的交替R结构的性质， 在一定的结晶条件下正常的血红蛋白。 的 计算将利用溶剂化分子动力学技术， 以及泊松-玻尔兹曼计算来估计静电 交互. 除了帮助了解 血红蛋白的结构/功能关系，该项目将提供新的 深入了解这些理论方法的能力， 描述了复杂蛋白质相互作用的细节。 血红蛋白和突变血红蛋白的研究具有重要的健康意义 影响有几个原因。 修饰的血红蛋白目前是 作为潜在的血液替代品的巨大兴趣，以及成功的预测 这些特性将有助于它们的设计。 更一般地说，血红蛋白 为蛋白质工程的基础研究提供了极好的机会， 因为已经分离出数百种突变体，其中60多种 已经进行了广泛的物理表征。 血红蛋白也是研究亚基/亚基的一个很好的测试案例 关联;这种相互作用涉及许多监管 事件，以及对蛋白质所涉及的原理的更深入理解- 蛋白质识别对于理解 生化控制机制

Computer simulations will be used to investigate structure/function relationships in human hemoglobin. The calculations will make use of modern simulation methods of estimating free energy changes, and continuum descriptions of some electrostatic interactions, to study the interaction of hemoglobin with protons and anions, the energetics of dissociation of tetramers into dimers, and the structural forces following ligand binding to the T quaternary state. These detailed investigations are made feasible by recent advances in computing power and in simulation algorithms, and by corresponding advances in high- resolution X-ray diffraction studies of mutant and partially liganded hemoglobins. These developments, plus a large body of evidence collected over the past decade on the properties of mutant hemoglobins, make possible a variety of tests of our ability to understand subunit association and allosteric interactions at an atomic level of detail. Specific interactions to be studied included: (a) binding of protons and anions to the R and T quaternary states; (b) energetics of tetramer/dimer dissociation in normal and mutant hemoglobins; (c) structural and energetic consequences of binding ligands to T state structures; and (d) properties of the alternate R structure seen in hemoglobin Ypsilanti and in normal hemoglobin under certain crystallization conditions. The calculations will make use of solvated molecular dynamics techniques as well as Poisson-Boltzmann calculations to estimate electrostatic interactions. In addition to helping to gain an understanding of structure/function relations in hemoglobin, the project will provide new insight into the ability of these sorts of theoretical methods to describe the details of complex protein interactions. Studies on hemoglobin and mutant hemoglobins have important health implications for several reasons. Modified hemoglobins are currently of great interest as potential blood substitutes, and successful predictions of such properties would aid in their design. More generally, hemoglobin offers an excellent opportunity for basic studies in protein engineering, since hundreds of mutants have been isolated, and over 60 of these have already been subjected to extensive physical characterization. Hemoglobin is also an excellent test case for studies of subunit/subunit association; such interactions are involved in a great many regulatory events, and a deeper understanding of the principles involved in protein- protein recognition could be of major benefit in understanding biochemical control mechanisms.