CONFORMATIONAL CONSEQUENCES OF A MEMBRANE ENVIRONMENT

在这项拨款申请中，一项旨在研究小肽（以及肽拟物）在小脂质囊泡、胶束和反胶束存在下的构象偏好的合作努力被描述。本研究利用了核磁共振、圆二色、电子顺磁共振、荧光、红外和拉曼光谱等多种光谱技术。为了改进生物分子的结构，将进行大量的计算，包括分子动力学模拟、基于距离几何的计算和从头计算，以确定小肽或拟肽物的正常模式和原理拉伸频率。从这些研究中，膜环境的影响，在不同水平的水合作用下，对小肽和拟肽物的构象偏好将被确定。考虑到许多这些候选药物的受体是膜相关的，这一信息对于确定在初始结合过程中首次呈现给受体的构象至关重要。此外，反胶束样环境已被用于跨膜递送。我们的结果将揭示交付材料的结构偏好。

In this grant application, a collaborative effort aimed at examining the conformational preferences of small peptides (as well as peptidomimetics) in the presence of small lipid vesicles, micelles, and reverse micelles is described. This research effort utilizes many spectroscopic techniques including nuclear magnetic resonance, circular dichroism, electron paramagetic resonance, fluorescence, infrared and Raman spectroscopy. For the refinement of the structures of the biomolecules, extensive computations will be carried out including molecular dynamics simulations, distance geometry-based calculations, and ab initio calculations for determination of the normal modes and principle stretching frequencies of the small peptides or peptidomimetics. From these studies the effects of the membrane environment, at differing levels of hydration, on the conformational preferences of small peptides and peptidomimetics will be ascertained. Considering that the receptor for many of these drug-candidates is membrane associated, this information is vital for the determination of the conformations first presented to the receptors during the initial binding process. In addition, reverse micelle-like environments have been utilized for delivery across membranes. Our results will shed insight into the structural preferences of the delivered material.