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

该项目的目标是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化学计划共同支持，基于电荷平衡形式主义，适用于经典的统计力学计算，特别关注膜和整合膜蛋白，并将其应用于研究离子在一个简单的，模型离子通道，短杆菌肽A，它一直存在长期的指示，需要明确的处理电子极化，定量描述通道电导来自详细的，全原子分子动力学模拟计算的平均力的潜力。该项目将建立在正在进行的第一代蛋白质可极化力场的初步工作的基础上;主要集中在推导脂质和膜双层组分的相关参数以及一系列单价离子。这将涉及应用量子力学和经典模拟（纯散装液体的MD）的组合，以确定定义的CHARMM-FQ电位的静电和非键参数。修改后的力常数的分子内的潜力，力场将通过应用到模拟的脂质双层膜模型进行验证。最后，伞形采样方法将被用来计算一系列单价离子通过短杆菌肽A通道的平均力的潜力，这对生物制药学家的一般科学界，特别是对那些建模膜系统，如离子通道和转运蛋白，有着广泛的影响。严格发展和应用生物大分子体系的极化力场是推进对这些体系理解的必要步骤。此外，对于离子通道，从使用可极化力场的模拟中收集大量信息，因为这种系统的物理学严重依赖于将由可极化相互作用势提供的相互作用之间的精确平衡。这项研究还为博士后学者和研究生提供了教育和培训机会。由于方法的广泛性，（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），需要解决力场发展和应用于离子通道的各个方面，有巨大的学习空间;同样重要的是，各种技术的结合将使人们能够广泛了解现有技术在解决科学问题方面的相互联系，在这种情况下是在生物物理学的范围内。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（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).