Modeling protein-membrane interactions

多肽和蛋白质与脂质膜的相互作用是许多生物过程的关键。在过去的几年里，PI和他的团队开发了一种隐式膜模型（IMM1），通过溶剂化自由能项描述蛋白质-膜的相互作用。该模型考虑了表面、跨膜和偶极势的影响，还可以模拟不同形状的孔隙，使其成为同类模型中最全面的模型。该模型已被用于解决许多有趣的生物学问题，包括膜结合蛋白结构的测定和分析、跨膜螺旋关联和毒素的膜插入。在这个项目中，这个模型将在多个方向上进行扩展。对脂质头群区域的改进处理将产生更准确的界面结合结果。结合侧压效应将允许考虑脂质组成的影响。将该模型扩展到弯曲膜将允许研究膜曲率感知和产生的机制，这是内吞作用或蛋白质分选等过程的关键。此外，将建立洗涤剂的隐式溶剂化模型，旨在获得洗涤剂-肽复合物的结构信息，表征sds -变性状态，研究脂质环境对肽构象的影响。同时，这些方法将应用于重要的生物学问题，包括血凝素融合肽在双层、胶束和隐式模型融合杆中的结构，á-synuclein在不同曲率膜中的构象，以及粘菌素的开放通道状态。与实验小组的合作将提供理论和实验之间的协同作用。这项研究将在一个大多数学生属于代表性不足的群体的机构中进行，并且有几个项目支持本科生参与研究。到目前为止，已有几名高中、本科或研究生阶段的少数民族学生参与了本实验室开展的研究。该项目将培养纽约城市大学化学和生物化学博士课程分子生物物理学分支学科的博士生。该实验室开发的方法可通过CHARMM计划提供给研究界，学术界和工业界的理论家和实验人员可以使用这些方法来解决重要的生物学问题，例如膜蛋白结构预测或了解膜蛋白的作用机制。本项目由分子与细胞生物科学部分子生物物理集群和物理部生命系统物理学项目共同支持。

The interaction of peptides and proteins with lipid membranes is key to many biological processes. Over the past years the PI and his group have developed an implicit membrane model (IMM1) that describes protein-membrane interactions through a solvation free energy term. The model accounts for the effects of surface, transmembrane, and dipole potential and can also model pores of different shapes, making it the most comprehensive model of its kind. The model has been used to address a number of interesting biological problems, including the determination and analysis of membrane-bound protein structures, transmembrane helix association, and membrane insertion of toxins. In this project, this model will be extended in a number of directions. An improved treatment of the lipid headgroup region will yield more accurate results for interfacial binding. Incorporating lateral pressure effects will allow accounting for the effects of lipid composition. Extending the model to curved membranes will allow the study of the mechanism of membrane curvature sensing and generation, which are key in processes like endocytosis or protein sorting. In addition, implicit solvation models for detergents will be developed, aiming to obtain structural information on detergent-peptide complexes, characterize the SDS-denatured state, and study the effect of lipid environment on peptide conformation. At the same time, these methods will be applied to important biological problems, including the structure of the hemagglutinin fusion peptide in bilayers, in micelles, and in implicitly modeled fusion stalks, the conformation of á-synuclein in membranes of different curvature, and the open channel state of colicins. Collaborations with experimental groups will provide synergy between theory and experiment. This research will be carried out at an institution where the majority of the students belong to underrepresented groups and several programs support the participation of undergraduates in research. Several minority students at the high school, undergraduate, or graduate level have participated so far in the research carried out in this lab. This project will train Ph.D. students in the Molecular Biophysics subdiscipline of the Chemistry and Biochemistry doctoral programs at the City University of New York. The methods developed in this lab are available to the research community through the CHARMM program and can be used by theoreticians and experimentalists in academia and industry to address important biological problems, such as membrane protein structure prediction or understanding the mechanism of action of membrane proteins. This project is jointly supported by the Molecular Biophysics Cluster in the Division of Molecular and Cellular Biosciences and the Physics of Living Systems Program in the Physics Division.