A new allosteric model of hemoglobin: pressure and comp*

了解血红蛋白（Hb）的结构-功能关系具有重要的生物医学意义。Monod，Wyman和Changeux（MWC）的双态变构模型长期以来一直被用来提供各种各样的结构，平衡和动力学数据的描述合作氧结合血红蛋白。最近在上述母基金资助下进行的工作挑战了MWC模型的基本假设，并指出氧亲和力主要由四级结构决定。在我的实验室进行的工作表明，一个扩展的MWC变构模型是必要的，以充分考虑的变构效应引起的氧结合等温线的变化。这项建议的目的是调查功能的扩展MWC模型建议我们的配体结合的研究，采用实验和计算相结合的方法，旨在补充我们以前的工作，使用HbA杂交。它具有高分辨率FLN激光光谱实验方法，不仅用于获取振动分辨光谱，还用于进行压力研究。这一建议的基本独创性在于应用的光谱技术，旨在监测流体静压力作为热力学参数相结合的计算方法，旨在建模的影响，结合别构效应对血红蛋白的三级和四级结构。匈牙利实验室（Fidy）将进行高分辨率光谱学实验和压力研究以及计算工作。所需HbA混合物的合成将在我的实验室（Yonetani）以及FT-拉曼实验中完成。

Understanding the structure-function relationships of hemoglobin (Hb) is of great biomedical significance. The two-state allosteric model of Monod, Wyman, and Changeux (MWC) has long been used to provide a description of a wide variety of structural, equilibrium and kinetic data on cooperative oxygen binding to Hb. Recent work performed under the above-mentioned parent grant has challenged the fundamental assumption underlying the MWC model and stating that oxygen affinity is primarily determined by the quaternary structure. Work performed in my laboratory shows that an extended MWC allosteric model is required to fully account for the variation of oxygen binding isotherms induced by allosteric effectors. This proposal aims at investigating features of the extended MWC model suggested by our ligand binding studies using a combined experimental and computational approach designed to complement our previous work using HbA hybrids. It features a high-resolution FLN laser spectroscopy experimental approach which will be used - not only for the acquisition of vibronically-resolved spectra - but also to perform pressure studies. The essential originality of this proposal resides in the application of a spectroscopic technique designed to monitor hydrostatic pressure as a thermodynamic parameter combined to a computational approach aimed at modeling the effect of binding allosteric effectors on the Hb tertiary and quaternary structure. The Hungarian laboratory (Fidy) will carry out the high-resolution spectroscopy experiments and pressure studies as well as the computational work. The synthesis of the required HbA hybrids will be done in my laboratory (Yonetani) as well as the FT-Raman experiments.