All-atom models of peptide folding

描述(申请人提供)：蛋白质折叠被称为遗传学的后半部分。对能够形成稳定二级结构的小肽的稳定性和折叠机制的详细了解是全面阐明蛋白质折叠和错误折叠机制的重要一步。这位研究人员帮助开发的最新进展使研究微秒时间尺度的分子事件成为可能，这些事件导致形成具有蛋白质和溶剂的全原子表示的小蛋白质的自然状态。为了进一步加深我们的理解，我们将应用全原子分子动力学模拟，包括显式和连续溶剂模型，来表征与小肽的折叠和错误折叠相关的非自然状态。这项建议将逐步解决四个关键领域：1)螺旋肽，包括基于丙氨酸的肽(AK16，AQ16和FS-肽)的模拟将被用于研究螺旋二级结构的形成。将研究螺旋形成过程中的限速步骤。2)将研究β-发夹形成，以获得导致引发的分子事件、决定限速步骤的物理相互作用和折叠路径的信息。这些研究将使我们能够检验我们的方法在重要的α-螺旋和β-折叠构象上的平衡。3)以葡萄球菌蛋白A B结构域的C-末端螺旋-发夹(螺旋II和螺旋III)和三链反平行的β-折叠多肽为模型系统，研究三级接触及其在二级结构形成中的作用。这些研究将使我们能够对我们建模第三接触的方法的准确性进行严格的评估。与实验的比较，包括对我们模型预测能力的直接测试，将是我们研究的一个组成部分，并将有助于对该方法的密切审查。4)建立连续溶剂模型，用于分子动力学模拟。

DESCRIPTION (provided by applicant): Protein folding has been referred to as the second half of genetics. A detailed knowledge about the stability and folding mechanisms of small peptides that can form stable secondary structures is an important step toward a full elucidation of the mechanisms of protein folding and misfolding. Recent advances, which this investigator has helped to develop, have made it possible to study microsecond time-scale molecular events leading to the formation of a native-like state of a small protein with all-atom representation of both protein and solvent. To further advance our understanding, we will apply all-atom molecular dynamics simulations, with both explicit and continuum solvent models, to characterize the non-native states that are relevant to the folding and misfolding of small peptides. This proposal will incrementally address four key areas: 1) Simulations on helical peptides, including alanine-based peptides (AK16, AQ16, and Fs-peptides), will be used to study helical secondary structure formation. The rate-limiting steps in helix formation will be investigated. 2) a beta-hairpin formation will be studied to obtain information on the molecular events leading to the initiation, the physical interactions determining the rate-limiting steps, and the folding pathways. These studies will allow us to examine the balance of our approach in the important alpha-helical and beta-sheet conformations. 3) Tertiary contacts and their role in secondary structure formation will be studied using the C-terminal helix-hairpin (helices II and III) of the B domain of Staphylococcal protein A and the three-stranded anti-parallel beta-sheet peptides as model systems. These studies will allow a rigorous evaluation on the accuracy of our approach in modeling the tertiary contacts. Comparison with experiments, including direct tests on the predictive ability of our model will be an integral part of our study and will be instrumental for a close scrutiny of the approach. 4) Continuum solvent models will be developed for molecular dynamics simulations.