NOVEL PARADIGM FOR LONG TIME PEPTIDE/PROTEIN DYNAMICS

我们将应用我们的新范式来处理柔性肽和蛋白质的长时间动力学来描述几个生物系统的动力学，包括模型β-桶蛋白的展开。此外，我们将继续测试和增强蛋白质的适用性和效率。另外。我们会继续测试和提高这个理论的适用性和效率。该理论旨在描述没有单一天然结构的肽、具有柔性部分的蛋白质、蛋白质中结构域的相对运动以及蛋白质的解折叠的动力学。缺乏单一天然结构的肽的主要实例是淀粉样蛋白β-肽，其参与阿尔茨海默病发生的斑块形成，其可以采用无规卷曲、高螺旋或β-折叠结构（后者促进斑块形成）。该理论的目标是描述比分子动力学（MD）刺激更长的时间尺度上的动力学。应用将考虑神经递质，如甲硫氨酸脑啡肽和内皮素，与高血压，肾衰竭，心肌梗死等有关，和β桶蛋白的解折叠。与MD模拟所有这些系统的比较将提供明确的（没有可调参数）测试的理论，并将使其完善。该理论将统计力学中简化描述的一般原理与溶剂动力学的流体动力学模型相结合，并对所有假设进行了严格的检验和改进。计算将密切配合计划的实验探测肽动力学的谢勒（芝加哥）使用单分子光谱和飞秒红外泵浦探测各向异性方法。我们还将预测NMR实验，特别是考虑不同NMR数据之间和/或NMR和X射线数据之间存在差异的情况。

We will apply our novel paradigm for treating the long time dynamics of flexible peptides and proteins to describe the dynamics of several biosystems, including the unfolding of a model beta-barrel protein. In addition, we will continue to test and enhance the applicability and efficiency of the protein. In addition. we will continue to test and enhance the applicability and efficiency of the theory. This theory is designed to describe the dynamics of peptides with no single native structure, proteins with flexible portions, relative motions of domains in proteins, and the unfolding of proteins. A primed example of a peptide lacking a single native structure is the amyloid beta-peptide, involved in plaque formation occurring with Alzheimer's disease, which may adopt random coil-, khi- helical, or beta-sheet structures (the latter promotes plaque formation). The goal of the theory is to describe dynamics of time scales orders of magnitude longer than those accessible to molecular describe dynamics on time scales orders of magnitude longer than those accessible to molecular dynamics (MD) stimulations. Applications will consider neurotransmitters, such as met-enkephalin, and endothelins which are associated with hypertension, renal failure, myocardial infarction, etc., and the unfolding of a beta-barrel protein. Comparisons with MD simulations for all these systems will provide unambiguous (no adjustable parameters) tests of the theory and will enable its refinement. The theory merges general principles of reduced descriptions in statistical mechanics with hydrodynamic models for the solvent dynamics, and with the scrupulous testing and improvement of all assumptions. Computations will be closely coordinated with planned experimental probes of peptide dynamics by Scherer (Chicago) using single molecule spectroscopy and femtosecond infrared pump-probe anisotropy methods. We will also predict NMR experiments and especially consider cases where discrepancies exist between different NMR data and/or between NMR and X-ray data.