Effective Energy Functions for Proteins in Lipid Membranes

膜蛋白的实验工作面临许多技术挑战。因此，计算机建模可能在这一领域产生重要影响。在过去的几年里，PI和他的团队开发了一种隐式方法来模拟膜蛋白，通过在力场中加入一个术语来描述蛋白质在非均相膜环境中的溶剂化自由能。在之前的拨款期间，隐膜模型（IMM1）扩展到具有水孔的蛋白质，并纳入了膜表面电荷和跨膜电压的影响。该模型已被实现到CHARMM包中，并已被用于深入了解驱动跨膜螺旋结合的力。还开发了计算肽-肽结合和肽-膜结合的绝对自由能的方法。下一个赠款期的目标分为两类：方法和应用。方法上的改进包括：更精确地处理排列偶极子的溶剂化自由能，改进离子侧链的处理，包括远程贡献，盐依赖性，水/非水环境依赖性，对脂质排列势的需要的检查，偶极子势的结合，以及金属离子的隐式溶剂建模。其应用包括：预测和合理化突变对膜蛋白稳定性的影响，研究跨膜螺旋结合，预测外周膜蛋白的膜结合方式，模拟粘菌素型毒素的膜插入机制。这些研究将与实验组合作进行。这项研究将在一所大学进行，其中60%的学生属于代表性不足的群体，并且有几个项目支持本科生参与研究。该项目还将培养纽约市立大学分子生物物理学专业的博士生。所开发的方法可通过CHARMM计划提供给研究界，并可由学术界和工业界的研究人员使用。它们对理论家和实验家都很有用，并适用于重要的生物学问题，如膜蛋白结构预测，或了解膜蛋白的作用机制。该项目由生物科学理事会分子与细胞生物科学部的分子生物物理学和数学与物理科学理事会化学部的理论与计算化学项目共同支持。

Experimental work on membrane proteins faces many technical challenges. Therefore, computer modeling could have important impact in this field. Over the last few years the PI and his group have developed an implicit approach to modeling membrane proteins by adding to the force field a term that describes the solvation free energy of a protein in the heterogeneous membrane environment. In the previous grant period the implicit membrane model (IMM1) was extended to proteins with an aqueous pore and the effects of membrane surface charge and transmembrane voltage were incorporated. The model has been implemented into the CHARMM package and has been used to obtain insights into the forces that drive transmembrane helix association. Methods have also been developed for the calculation of absolute free energies for peptide-peptide association and peptide-membrane binding. The goals for the next grant period fall into two categories: methodology and applications. The methodological improvements include: a more accurate treatment of the solvation free energy of aligned dipoles, an improved treatment of the ionic sidechains incorporating long-range contributions, salt dependence, aqueous/nonaqueous environment dependence, examination of the need for a lipid alignment potential, incorporation of the dipole potential, and implicit solvent modeling of metal ions. The applications include: prediction and rationalization of the effect of mutations in membrane protein stability, studies of transmembrane helix association, prediction of the membrane binding mode of peripheral membrane proteins, and modeling the membrane insertion mechanism of colicin-type toxins. These studies will be carried out in collaboration with experimental groups.This research will be carried out at an institution where 60% of the students belong to underrepresented groups and several programs support the participation of undergraduates in research. The project will also train Ph.D. students in the Molecular Biophysics program at CUNY. The methods developed are available to the research community through the CHARMM program and can be used by researchers in academia and industry. They are useful to theoreticians and experimentalists alike and are applicable to important biological problems, such as membrane protein structure prediction, or understanding the mechanism of action of membrane proteins. This project is jointly supported by Molecular Biophysics in the Division of Molecular and Cellular Biosciences in the Directorate for Biological Sciences and the Theoretical and Computational Chemistry Program in the Division of Chemistry in the Mathematical and Physical Sciences Directorate.