Polarizable Force Field for Proteins and Lipids

描述（由申请人提供）：本提案的目标是阐明凝聚生物分子系统中诱导极化的本质，并完成第一代蛋白质和磷脂膜的全原子极化力场。我们已经采用并开始开发一种利用经典德鲁德振荡器结合电子极化率的势函数。我们已经优化了一个简单的水模型（SWM4-DP），现在准备进入下一阶段。我们的第一个目标是通过优化一些碱性化合物的力场来阐明相对于气相的凝聚相诱导极化的性质。这些初步的研究也将有助于澄清由泡利不相容原理和电子云重叠引起的凝聚系统中诱导电子极化率的基本降低。我们的第二个目标是优化力场的内部部分。我们的第三个目标是通过在晶体环境中对一组蛋白质进行分子动力学模拟来评估力场的准确性。此外，脂质膜界面电位的性质将通过对脂质双分子层的完全极化模型和钙与钙结合蛋白中ef -手的阳离子-配体相互作用的MD模拟来阐明。重要的是要强调，拟议研究中的三个目标是以迭代的方式联系在一起的。在完成拟议的研究后，科学界将获得一种新的蛋白质和脂质力场，其中包括电子极化性的明确处理。虽然拟议的研究将使用CHARMM程序进行，但用于处理电子极化的经典德鲁德振荡器的简单性将确保所开发的力场可以很容易地在其他模拟软件包中实现。

DESCRIPTION (provided by applicant): The goal of this proposal is to elucidate the nature of induced polarization in condensed biomolecular systems and to complete a first generation all-atom polarizable force field for proteins and phospholipid membranes. We have adopted and started to develop a potential function that incorporates electronic polarizability using classical Drude oscillators. We have optimized a simple water model (SWM4-DP) and are now ready to move to the next phase. Our first aim will be to elucidate the nature of induced polarizability in condensed phases relative to the gas phase by optimizing the force field for a number of basic compounds. These initial studies will also help clarify the fundamental reduction of induced electronic polarizability in condensed systems caused by Pauli's exclusion principle and the overlap of electronic clouds. Our second aim will be to optimize the internal portion of the force field. Our third aim will be to assess the accuracy of the force field by performing molecular dynamics simulations of a test suite of proteins in the crystal environment. In addition, the nature of the interfacial potential of lipid membranes will be elucidated by performing a MD simulation of a fully polarizable model of a lipid bilayer and of the cation-ligand interactions giving rise to cooperative binding of calcium to the EF-hands in calbindin. It is important to emphasize that the three aims in the proposed study are linked in an iterative fashion. Upon completion of the proposed study a novel force field for proteins and lipids that includes explicit treatment of electronic polarizability will be available to the scientific community. While the proposed studies will be performed using the program CHARMM, the simplicity of the classical Drude oscillator used to treat electronic polarizability will insure that the developed force field may be readily implemented in other simulation packages.