CAREER: Biomolecular Simulations Coming to Age: Folding of Globular and Membrane-bound Proteins Studied by Computer

这个项目由分子和细胞生物科学部的分子生物物理学和化学部的理论和计算程序共同支持，将使用新的计算机模拟技术来研究蛋白质折叠的机制。采用的主要计算算法是长度随机差分方程法(SDEL)，这是一种允许计算连接系统两个已知(边界)状态的轨迹的边值方法。这种方法可以用原子细节来观察以前不可能通过计算机模拟来研究的长期动态过程。通过显式模拟水分子，研究水环境中球形单结构域蛋白(无肌红蛋白和牛β-乳球蛋白)和多结构域蛋白(噬菌体Fd基因3蛋白和磷酸甘油酸激酶)的折叠过程。这些系统中的大多数以前都没有被计算机模拟研究过，因为它们的体积大，折叠时间慢。此外，基于连续介质介电处理的隐式水/膜模型(广义Born理论)将被用来以前所未有的细节研究膜结合的多肽和蛋白质的插入和折叠。首先将考虑蜂毒素等简单多肽的嵌入和折叠以及血糖素A的二聚体跨膜结构域。稍后，将研究更复杂和生物相关的蛋白质的折叠模拟，如K+通道KSCA、单体β-桶OmpA孔蛋白和细菌视紫红质。该项目将促进研究生和本科生的培养。这些研究和方法将被用作南佛罗里达大学教师研究体验计划的主题材料，学校教师将根据暑期进行的研究为他们的课堂设计教案。教师研究体验计划有可能通过他们的老师设计的课程向许多初中生灌输对科学的热爱。此外，坦帕地区拉美裔学生的成功和他们进入大学的入学将通过参加南佛罗里达大学的一个特殊社会项目得到支持。

This project, jointly supported by Molecular Biophysics in the Division of Molecular and Cellular Biosciences and the Theoretical and Computational Program in the Chemistry Division, will use novel computer simulation techniques to study the mechanism of folding of proteins. The main computational algorithm to be employed is the stochastic difference equation in length (SDEL), a boundary value method that permits the calculation of trajectories connecting two known (boundary) states of the system. This methodology allows viewing, with atomic detail, long time dynamical processes that were impossible to study before by computer simulations. The folding process of globular single-domain proteins (apomyoglobin and bovine beta-lactoglobulin) and multi-domain proteins (gene-3 protein of phage fd and the phosphoglycerate kinase) will be considered in aqueous environment by simulating explicitly the water molecules. Most of these systems have not been studied before by computer simulations because of their large size and their slow folding times. Also, an implicit water/membrane model based on a continuum dielectric treatment (the Generalized Born theory) will be used to study the insertion and folding of membrane-bound peptides and proteins with unprecedented detail. The embedding and folding of simple peptides like mellitin and the dimeric transmembrane domain from glycophorin A will be considered first. Later on, folding simulations of more complex and biologically relevant proteins like the K+ channel KscA, the monomeric beta-barrel OmpA porin and Bacteriorhodopsin will be studied. This project will promote the training of graduate and undergraduate students. The research and methodologies will be used as thematic material in the Research Experience for Teachers program at the University of South Florida in which school teachers design lesson plans for their classrooms based on research performed during the summer. The Research Experience for Teachers program has the potential to instill in many middle and high school students the love for science through the lessons designed by their teachers. Also, the success of Hispanic school students in the Tampa area and their enrollment to college will be supported through participation in a special social program at the University of South Florida.