Nature's Rotary Molecular Dynamos: A Systematic Modeling Framework

每个生物细胞的工作都是由蛋白质、RNA或它们的组合组成的“分子机器”完成的。这个项目将使用基于物理的计算方法来研究这些机器是如何工作的。该项目的重点将是“旋转ATPase”，它可以将一种类型的化学能转化为另一种--从跨膜pH差转化为众所周知的电池“分子燃料”--三磷酸腺苷。该项目将开发机器的数学模型，以便：(I)了解这些机器在细胞遇到的各种条件下如何工作(和故障)的生物物理学；以及(Ii)开发更强大的建模方法，可用于其他机器的研究。该项目还将继续开发一种在线教科书，涵盖细胞分子机器的生物物理学。这项工作将加强基于物理的分子机器建模策略。新的元素包括对替代机制的系统探索，以进化为动力的约束优化取代参数拟合，可逆性检查，以及对广泛的条件和化学计量的考虑。从生物学上讲，这项工作可以为许多不确定的参数提供最佳和有限的范围，并明确地分离出在物种特定的化学计量和细胞器特定的方向性(合成与泵送)的广泛范围内的适应。对替代机制和假设机制的考虑也有助于理解旋转合酶出现之前的ATP合成的进化史，以及有助于其他分子机器家族的研究。该项目还将进一步开发一本免费的在线细胞生物物理学书籍(PhysicalLensOnTheCell.org)，扩大所涵盖的主题，并部分根据将要进行的研究增加交互式数值模型。

The workings of every biological cell are carried out by "molecular machines" made up of proteins, RNA or combinations of these. This project will investigate how such machines function using physics-based computational methods. The project's focus will be the "rotary ATPases", which can convert one type of chemical energy into another - from a transmembrane pH difference into ATP, the well-known "molecular fuel" of the cell. The project will develop mathematical models of the machines in order to: (i) understand the biophysics of how these machines function (and malfunction) over a wide range of conditions encountered by the cell; and (ii) develop more powerful modeling approaches that are transferable to the study of other machines. The project will also continue development of an online textbook covering the biophysics of the cell's molecular machines.The work will enhance physics-based strategies for modeling molecular machines. Novel elements include systematic exploration of alternative mechanisms, evolution-motivated constrained optimization in place of parameter fitting, examination of reversibility, and consideration of a wide range of conditions and stoichiometries. Biologically, the work can provide optimal and limiting ranges for many uncertain parameters, and explicitly disentangle adaptations in the wide range of species-specific stoichiometries and organelle-specific directionality (synthesis vs. pumping). The consideration of alternative and hypothetical mechanisms could also contribute to understanding the evolutionary history of ATP synthesis, prior to the advent of the rotary synthase, as well as aiding the study of other families of molecular machines. The project will also lead to further development of a free online cell biophysics book (PhysicalLensOnTheCell.org), expanding the topics covered and adding interactive numerical models, based in part on the research to be performed.