Polarizable Force Fields for Biological Molecules: Applications to Integral Membrane Ion Channels

该项目由分子与细胞生物科学部的分子生物物理学和化学部的理论与计算化学项目共同支持，其目标是基于电荷平衡形式建立一个极化的CHARMM力场，适用于经典的统计力学计算，特别关注膜和整体膜蛋白，并将其应用于研究简单，模型离子通道，Gramicidin A，长期以来一直有迹象表明，需要明确处理电子极化，以定量描述从详细的全原子分子动力学模拟计算的平均力势推导出的通道电导。该项目将建立在正在进行的第一代蛋白质极化力场的初步工作基础上；主要集中于推导脂质和膜双层组分的相关参数，以及一系列的单价离子。这将涉及量子力学和经典模拟（纯散装液体的MD）相结合的应用，以确定定义CHARMM-FQ势的静电和非键参数。在修改分子内电位的力常数后，将通过应用于脂质双层膜模型的模拟来验证该力场。最后，将采用伞采样方法来计算一系列单价离子通过Gramicidin a通道转移的平均力势。这对生物物理学家的一般科学界，特别是对离子通道和转运体等膜系统的建模有重大的潜在影响。对大型生物大分子系统的极化力场的严格开发和应用是促进对这些系统的理解的必要步骤。此外，对于离子通道，有大量的信息需要从使用极化力场的模拟中收集，因为这种系统的物理特性严重依赖于极化相互作用势提供的相互作用之间的精确平衡。本研究还为博士后学者和研究生提供教育和培训机会。由于需要广泛的方法（从从头算/DFT方法到基于连续统的宏观方法，如布朗动力学和电扩散理论）来解决力场发展和离子通道应用的各个方面，因此有巨大的学习空间；同样重要的是，技术的整合将允许对解决科学导向问题的现有技术之间的相互联系有一个广泛的理解，在这种情况下是在生物物理学领域内。最后，所有与CHARMMFQ力场相关的代码开发和力场参数将通过CHARMM学术许可证的分发和我们的网站（用于力场参数）提供给学术实验室。

The objective of this project, jointly supported by Molecular Biophysics in the Division of Molecular and Cellular Biosciences and the Theoretical and Computational Chemistry Program in the Chemistry Division, is to develop a polarizable CHARMM force field, based on the charge equilibration formalism, applicable to classical statistical mechanical computations with a particular focus on membranes and integral membrane proteins and to apply it to study ion translocation properties in a simple, model ion channel, Gramicidin A, for which there has been long-standing indication of the need for explicit treatment of electronic polarization to quantitatively describe channel conductance derived from potentials of mean force computed from detailed, all-atom molecular dynamics simulations. The project will build on ongoing preliminary work toward a first-generation polarizable force field for proteins; focusing predominately on deriving relevant parameters for lipids and membrane bilayer components, and a series of monovalent ions. This will involve application of a combination of quantum mechanical and classical simulations (MD of pure bulk liquids) to determine the electrostatic and non-bonded parameters defining the CHARMM-FQ potential. Following modification of force constants of intramolecular potentials, the force field will be validated via application to simulations of lipid bilayers as membrane models. Finally, umbrella-sampling methods will be employed to compute a potential of mean force for a series of monovalent ions translocating through the Gramicidin A channel.There is significant potential for broad impact on the general scientific community of biophysicists, and more specifically on those modeling membrane systems such as ion channels and transporters. The rigorous development and application of polarizable force fields for to large biomacromolecular systems is a necessary step in advancing understanding of these systems. Furthermore, for ion channels there is a vast amount of information to be gleaned from simulations using polarizable force fields, since the physics of such systems is critically dependent on a precise balance between interactions that will be provided by polarizable interaction potentials. This research also provides educational and training opportunities for postdoctoral scholars and graduate students. Due to the broad spectrum of methodologies (ranging from ab initio/DFT methods to continuum based macroscopic methods such as Brownian Dynamics and electro-diffusion theory) required to address the various aspects of force field development and application to ion channels, there is tremendous scope for learning; equally important, the integration of techniques will allow a broad understanding of the interconnections of available technologies in solving scientifically oriented problems, in this case within the realm of biophysics. Finally, all of the code development and force field parameters associated with the CHARMMFQ force field will be available to academic laboratories via distribution of the CHARMM academic license and from our web site (for the force field parameters).