Modeling protein-membrane interactions

多肽和蛋白质与脂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个隐式膜模型(IMM1)，该模型通过一个溶剂化自由能项来描述蛋白质-膜相互作用。该模型考虑了表面、跨膜和偶极电势的影响，还可以模拟不同形状的孔，使其成为同类模型中最全面的。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、跨膜螺旋结合和毒素的膜插入。在这个项目中，这一模式将在多个方向上进行扩展。改进对脂头基团区域的处理将产生更准确的界面结合结果。考虑侧向压力的影响将可以考虑脂质成分的影响。将该模型扩展到弯曲的膜将允许研究膜的曲率传感和产生的机制，这是内吞或蛋白质分选等过程中的关键。此外，还将建立洗涤剂的隐式溶剂化模型，以获得洗涤剂-多肽复合体的结构信息，表征十二烷基硫酸钠的变性状态，并研究脂环境对肽构象的影响。同时，这些方法将被应用于重要的生物学问题，包括血凝素融合肽在双层、胶束和隐式模拟融合柄中的结构，α-突触核蛋白在不同曲率的膜中的构象，以及粘连素的开放通道状态。与实验小组的合作将提供理论和实验之间的协同效应。这项研究将在一所学校进行，在那里，大多数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。到目前为止，有几个少数民族学生在高中、本科生或研究生水平上参与了这个实验室进行的研究。该项目将培养纽约市立大学化学和生物化学博士项目分子生物物理学分支学科的博士生。通过CHARMM计划，该实验室开发的方法可供研究界使用，学术界和工业界的理论家和实验者可以使用这些方法来解决重要的生物学问题，如膜蛋白结构预测或了解膜蛋白的作用机制。该项目由分子和细胞生物科学部的分子生物物理组和物理部的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.