Understanding protein folding and function via molecular simulation

通过分子模拟了解蛋白质折叠和功能

• 批准号: 8762025
• 负责人: Robert Best
• 金额: $ 73.68万
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8762025
• 关键词: Address; Data; Development; Disease; Goals; Methodology; Methods; Modeling; Molecular; Molecular Models; Property; Protein Dynamics; Proteins; Resolution; Role; Solvents; Spectrin; Testing; Water; Work; chaperonin; design; improved; insight; interest; models and simulation; molecular modeling; next generation; novel; prevent; protein folding; protein function; protein misfolding; research study; simulation; success; theories

In the past year, this project has addressed several problems and methodological challenges in protein folding, most significantly: 1. Methodology for protein folding simulations. A description of protein folding or misfolding using atomistic simulations relies on the quality of the simulation model. Despite recent successes in ab initio folding simulations, there are still outstanding problems with the simulation models. These have been addressed here at a number of levels. At the most detailed, we have contributed to the development of the next generation of polarizable energy functions, which in principle should provide the most accurate description of the protein energy landscape (12). We have also worked to develop simpler, but more inexpensive computationally methods: firstly, by parametrizing non-polarizable models to match polarizable ones (2) and secondly, by developing models in which the solvent does not need to be explicitly modelled (7). These advances should ultimately result in a more reliable description of protein dynamics and function. 2. Protein folding mechanism. We have used molecular simulation models to test current protein folding theory. This has included a direct test of some key assumptions of the theory against a set of detailed atomistic simulations of nine different proteins in explicit water. We have found that the assumptions of the theory hold for naturally occurring proteins, the only exceptions being for simplified, designed proteins (6). We have further tested the theory against experimental data, by using the assumptions of the theory in simulations to predict the folding mechanism of spectrin domains (5). These results help to justify the use of simplified molecular models to provide insight into protein folding and function (10). 3. Role of molecular chaperonins in protein folding. We have used simulation and theory in order to analyze the effect of passive confinement inside chaperonins such as GroEL on protein folding. We have been able to explain experimental observations on folding rates inside chaperonins, and to propose a specific mechanism by which chaperonins can prevent misfolding in multidomain proteins.

在过去的一年里，该项目解决了几个问题， 蛋白质折叠的挑战，最重要的是： 1.蛋白质折叠模拟方法。蛋白质折叠或 使用原子模拟的错误折叠依赖于模拟模型的质量。 尽管最近在从头折叠模拟方面取得了成功，但仍然存在一些突出的问题。 模拟模型的问题。这些问题已在多个层面上得到解决。 在最详细的，我们已经为下一代的发展作出了贡献 的极化能量函数，这在原则上应该提供最准确的 蛋白质能量景观的描述（12）。我们还致力于开发 更简单，但更便宜的计算方法：首先，通过参数化 非极化模型匹配极化模型（2），其次，通过开发 模型，其中溶剂不需要明确建模（7）。这些 这些进展最终将导致对蛋白质动力学的更可靠的描述 和功能 2.蛋白质折叠机制。我们用分子模拟模型来测试 蛋白质折叠理论这包括直接测试一些关键的 假设的理论对一组详细的原子模拟， 九种不同的蛋白质我们发现， 该理论适用于自然发生的蛋白质，唯一的例外是 对于简化的，设计的蛋白质（6）。我们进一步测试了这个理论， 实验数据，通过使用模拟中的理论假设， 预测血影蛋白结构域的折叠机制（5）。这些结果有助于 证明使用简化的分子模型来深入了解蛋白质是合理的 功能与功能（10） 3.分子伴侣蛋白在蛋白质折叠中的作用。我们使用了模拟和 理论，以分析伴侣蛋白内的被动限制的效果 例如GroEL对蛋白质折叠的影响。我们已经能够解释实验 观察分子伴侣蛋白内部的折叠速率，并提出一个具体的 伴侣蛋白防止多结构域错误折叠的机制 proteins.