Establishing the link between biomolecular dynamics and function from an atomistic perspective

细胞内生物过程的调节依赖于生物分子之间的物理相互作用以及由此产生的生物分子动力学和构象(形状)的变化。这些过程反过来调节生物分子在细胞不同区域内的重新定位，加快生化反应，开启和关闭基因表达，并帮助其他蛋白质的正确折叠。仅生物分子的三维结构和功能之间的关系不足以完全解释这些过程的分子基础。生物分子不是静态的，而是固有的柔性，尽管越来越多的实验和理论研究，但生物分子运动在生物功能调节中的作用仍然不清楚。无法区分不同因素对整体功能的贡献是问题的核心。这个研究项目的目标是建立生物分子运动的分子基础，这些分子参与了生物过程。开发的计算工具将公开提供，并被实施到广泛使用的开放计算软件中，供任何人使用和改进。这项研究将提供一个极好的机会来吸引和培训下一代科学家。这项研究的一个优势是它跨越了许多学科，包括化学、生物、物理、数学和计算机科学，因此提供了一个极好的机会来吸引学生进入科学和科学研究。生物分子的结构和功能之间的关系已经很好地建立了，然而，这些信息并不总是足以提供对生物分子过程机制的完整理解。因此，变构和酶机制中的结构、动力学和功能之间的关系还远未完全了解。取得进展的关键障碍是缺乏对动态运动在生物分子功能中的作用的基本了解，以及无法在实验上描述生物分子在原子分辨率下的时间行为。该项目的目标是在复杂的生物分子组装中建立生物系统中动态和变构调节的分子基础，包括协同底物结合和瞬时蛋白质-蛋白质相互作用。具体地说，这项研究使用理论和计算机模拟作为各种实验的补充工具，包括核磁共振、X射线结晶学和表面等离子体共振，以了解多结构域酶Pin1和转录因子共调节因子Pirin中的变构调节。其主要目标是识别调节功能的残基-残基相互作用的动态网络，在定量的水平上描述其特征，并探索获得长时间尺度动力学的计算方法，克服传统直接模拟方法的局限性。对上述系统的原子细节的计算研究将使我们能够理解一个区域的动力学调制是如何通过氨基酸残基的动态网络传递到空间远端区域的。这项研究将加强生物分子动力学在解释实验结果方面的结合。这项研究将提供建立亚细胞过程中动力学、结构和功能之间关系所需的基本知识。该项目由生物科学局分子和细胞生物科学部的分子生物物理组和数学和物理科学局化学部的化学理论、模型和计算方法计划共同资助。

Regulation of biological processes in the cell relies on physical interactions between biomolecules and on the resulting changes in the dynamics and conformations (shape) of the biomolecules. These processes in turn regulate relocation of biomolecules within different regions of the cell, speed up biochemical reactions, turn on and off gene expression, and aid the correct folding of other proteins. The relationship between three-dimensional structures and function of biomolecules alone is insufficient to fully explain the molecular basis of these processes. Biomolecules are not static but inherently flexible, and the role of biomolecular motions in the regulation of biological functions has remained unclear, despite an increasing number of experimental and theoretical studies. The inability to separate out the contributions of different factors to overall function is at the heart of the problem. The goal of this research project is to establish the molecular basis of the motions of biomolecules involved in biological processes. Computational tools that are developed will be publicly available and implemented into widely used open computational software for anyone to use and improve upon. The research will provide an excellent opportunity to attract and train the next generation of scientists. An advantage of the research is that it cuts across many disciplines, including chemistry, biology, physics, mathematics, and computer science, and, therefore, provides an excellent opportunity to attract students into the sciences and scientific research. The relationship between structure and function in biomolecules is well established, however, this information is not always adequate to provide a complete understanding of the mechanism of biomolecular processes. The relationship between structure, dynamics and function in allostery and enzyme mechanisms is therefore far from being fully understood. Critical barriers to progress are the lack of fundamental understanding of the role of dynamical motions in biomolecular function and the inability to experimentally describe temporal behaviors of biomolecules at atomic resolution. The goal of this project is to establish the molecular basis of dynamical and allosteric regulation in biological systems involving cooperative substrate binding and transient protein-protein interactions in complex biomolecular assemblies. Specifically, the research uses theory and computer simulations as complementary tools to a variety of experiments, including NMR, X-ray crystallography and Surface Plasmon Resonance, to understand allosteric regulation in a multi-domain enzyme, Pin1, and a transcription factor co-regulator Pirin. The main objectives are to identify dynamical networks of residue-residue interactions that regulate function, to describe their characteristics on a quantitative level, and to explore computational approaches to access long time scale dynamics, overcoming limitations of traditional direct simulation methods. Computational investigation of the above systems in atomic detail will allow understanding of how modulation in dynamics in one region is communicated via a dynamical network of amino acid residues to a spatially distal region. The research will enhance the incorporation of biomolecular dynamics in interpreting experimental results. The research will provide the fundamental knowledge needed to establish the relationship between dynamics, structure, and function in sub-cellular processes. This project is jointly funded by the Molecular Biophysics Cluster in the Division of Molecular and Cellular Biosciences in the Directorate for Biological Sciences and the Chemical Theory, Models, and Computational Methods Program in the Division of Chemistry in the Directorate of Mathematical and Physical Sciences.