COMPUTER SIMULATION OF HEMOGLOBIN ELECTROSTATICS

将使用计算机模拟来研究结构/功能 人类血红蛋白之间的关系。这些计算将利用 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，以研究 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和结构作用力 在配体结合到T四元状态之后。这些详细信息 计算能力的最新进展使研究成为可能 以及在模拟算法方面，以及在高 突变体和部分配体的分辨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 在过去的十年里，关于突变的血红蛋白的性质， 可能对我们理解亚单位的能力进行各种测试 原子细节水平上的缔合和变构相互作用。 需要研究的具体相互作用包括：(A)质子结合和 R和T季态的阴离子；(B)四聚体/二聚体的能量学 正常和突变的血红蛋白中的解离；(C)结构和 配体与T态结构结合的能量后果；和(D) 血红蛋白Ypsilanti和Ypsilanti中交替R结构的性质 在一定结晶条件下的正常血红蛋白。这个 计算将利用溶剂化分子动力学技术，如 用泊松-玻尔兹曼计算估算静电 互动。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 洞察这些理论方法的能力 描述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 这其中蕴含着几个原因。经修饰的血红蛋白目前 作为潜在的血液替代品的极大兴趣，并成功预测 这样的房产将有助于它们的设计。更普遍的是，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个突变体，其中60多个已经 已经受到了广泛的身体特征的影响。 对于亚基/亚单位的研究，血红蛋白也是一个很好的测试案例。 协会；这样的相互作用涉及大量的监管 事件，以及对蛋白质所涉及的原理的更深层次的理解- 蛋白质识别可能对理解 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.