Multi-scale simulation methods for energy transduction and macromolecular assembly

威斯康星大学的强崔得到了化学理论、模型和计算方法计划的支持，该计划旨在开发有效的分子模拟方法，以解决涉及多个长度尺度的重要且具有挑战性的生物物理和化学问题。该奖项是由分子和细胞生物学部门的生物物理学项目共同资助的。生物能量传递是生命中最令人着迷的方面之一，它是一种能量传输方式，其中能量的形式也发生了变化。生物分子马达和泵以惊人的效率将能量从一种形式转化为另一种形式。研究生物分子离子泵中的能量传递涉及发展量子力学和经典模型，以恰当地描述跨膜蛋白质内部离子传输的能量学和效率。大分子组装问题是许多令人着迷的生物学过程的基础，如肌肉纤维的形成，这需要开发有效的粗粒度模型，达到计算效率和生物物理特异性之间的平衡。该项目为希望在化学、生物和工程交叉领域工作的所有级别的学生提供研究机会。崔博士积极参与旨在扩大代表不足的少数民族成员对物理和生物科学的参与的项目。对于离子泵问题，通过采用最小自由能路径方法和多层量子力学/分子力学(QMMM)模型，崔博士和他的同事可以显著提高研究复杂生物分子中远程质子转移的精度和采样。通过采用化学势均衡方案来表示不同QM区域的极化，它们可以很好地描述离子通过富含极性基序和带电基序的跨膜蛋白内部的传输。该计算框架首次尝试在QM/MM类型的模拟中包括膜电位。对于螺旋线圈组装问题，它描述了一类广泛的问题，其中生物分子的适当组装严重依赖于其结构的有限程度的灵活性，他们提出的多极粗粒度模型利用透明的参数化框架在原子表示和粗粒度表示之间建立了自然的联系。与连续介质力学模型相比，该模型可以获得相似的长度和时间尺度，但可以使用标准的分子模拟软件进行有效的研究。

Qiang Cui, of the University of Wisconsin, is supported by an award from the Chemical Theory, Models and Computational Methods program to develop effective molecular simulation methodologies to tackle important and challenging biophysical and chemical problems that involve multiple length scales. The award is cofunded by the Biophysics Program in the Division of Molecular and Cellular Biology. Bioenergy transduction, a type of energy transport in which the form of the energy also changes, is one of the most fascinating aspects of life. Biomolecular motors and pumps transduce energy from one form to the other with remarkable efficiency. The study of energy transduction in biomolecular ion pumps involves developing quantum mechanical and classical models that properly describe the energetics and efficiency of ion transport through the interior of a transmembrane protein. The problem of macromolecular assembly, which underlies many fascinating biological processes such as the formation of muscle fiber, requires the development of effective coarse-grained models that strike the balance of computational efficiency and biophysical specificity. The project offers research opportunities for students at all levels who wish to work at the intersection of chemistry, biology and engineering. Dr. Cui is actively engaged with programs aimed at broadening participation in physical and biological science by members of under-represented minorities.For the problem of ion pumping, by adopting the minimum free energy path approach and a multi-layer Quantum Mechanics/Molecular Mechanics (QMMM) model, Cui and co-workers can significantly improve the accuracy and sampling for the study of long-range proton transfers in complex biomolecules compared to previous efforts. By adopting the chemical potential equalization scheme to represent the polarization of different QM regions, they can properly describe ion transport through the interior of a transmembrane protein that is rich in polar and charged motifs. This computational framework represents the first attempt to include the membrane potential in QM/MM type of simulations. For the problem of coiled-coil assembly, which describes a broad class of problems in which the proper assembly of biomolecules relies critically on a limited degree of flexibility in their structures, their proposed multipolar coarse-grained model makes a natural connection between atomistic and coarse-grained representations with a transparent framework for parameterization. Compared to continuum mechanics models, this model can access similar length and time scales but can be efficiently studied using standard molecular simulation software.