Multiscale modeling of liquid interfacial phases in biomolecular environments and nanomaterials

人们普遍认识到，溶剂化对广泛的科学技术至关重要。特别是，非均相液相在化学、电化学、生物催化、生物学和药理学的各种技术应用中具有至关重要的意义。代表性的例子是纳米多孔碳中的电解质溶液，以及细胞内限制下的蛋白质-药物相互作用。模拟界面和纳米约束下的液体已经尝试了不同程度的简化，从通过生物膜的药物运输估计为水和辛醇的散装液相之间的分配，到通过脂质双分子层的纳米颗粒转运的粗粒度模拟。***目前，在化学和生物分子体系以及纳米材料的纳米尺度约束中，需要充分包含溶剂分子结构的溶剂化理论模型。这样的理论模型对于扩展分子模拟的能力有很大的需求，到目前为止，分子模拟还不足以在整个范围内解决复杂的现象和过程，从快速到非常慢的大型纳米系统。***基于统计力学的第一原理，液体积分方程理论为处理溶液中复杂的化学和生物分子系统提供了坚实的平台。特别是，具有kovalko - hirata闭合关系的三维参考相互作用位点模型（3D-RISM-KH分子溶剂化理论）为溶液中的许多系统提供了机制见解和性质预测，否则可以进行分子模拟或连续溶剂化处理。3D-RISM-KH已经发展到实际应用的状态，并与量子化学、MD和DPD模拟方法以及配体对接协议的多尺度方法相结合，这些发展在主要软件包中实现：阿姆斯特丹密度函数（ADF）计算化学包、Amber MD包、对接工具AutoDock套件和分子操作环境（MOE）药物发现套件。***本项目将把3D-RISM-KH和SS-LMBW方法结合起来，建立一个关于液体界面和受限液体的非均匀3D-RISM-KH分子理论，并将其应用于复杂的化学和生物分子问题，包括：(i)用于阿尔茨海默氏症和渐冻症治疗的药物发现和跨生物膜和血脑屏障的转运；（ii）纤维素纳米晶体（CNC）纳米颗粒跨生物膜转运的纳米毒性数据库的预测；（iii）用于储能装置的纳米多孔碳材料中的纳米颗粒。新的方法开发将被添加到MOE（加拿大）和ADF（荷兰）软件包中的现有实现中。两名博士生将参与并接受该项目的培训。********

It is widely recognized that solvation is critical for a broad range of science and technology. In particular, inhomogeneous liquid phases are of paramount importance in a variety of technological applications of chemistry, electrochemistry, biocatalysis, biology, and pharmacology. Representative examples are electrolyte solution in nanoporous carbon, and protein-drug interactions in intracellular confinement. Modeling liquids at interfaces and in nano-confinement has been attempted at different levels of simplification, from drug transport across a biomembrane estimated as partitioning between bulk liquid phases of water and octanol, to coarse-grained simulations of nanoparticle translocation across a lipid bilayer.***At present, there is a need of solvation theoretical models that adequately include molecular structure of solvent in nanoscale confinement of chemical and biomolecular systems and nanomaterials. Such theoretical models are of great demand to extend the capabilities of molecular simulations which are by far not sufficient to address complex phenomena and processes on the whole spectrum of scales from fast to very slow in large nanosystems of interest.***Based on the first principles of statistical mechanics, integral equation theory of liquids provides a firm platform to handle complex chemical and biomolecular systems in solution. In particular, the three-dimensional reference interaction site model with the Kovalenko-Hirata closure relation (3D-RISM-KH molecular theory of solvation) has provided mechanisms insights and properties predictions for a number of systems in solution otherwise amenable to molecular simulation or continuum solvation treatment. 3D-RISM-KH has been advanced to the state of practical applicability and coupled in multiscale methodology with quantum chemistry, MD and DPD simulation methods, and ligand docking protocols the developments implemented in major software packages: Amsterdam Density Functional (ADF) computational chemistry package, Amber MD package, AutoDock suite of docking tools, and Molecular Operating Environment (MOE) drug discovery suite.***This project will couple the 3D-RISM-KH and SS-LMBW approaches in an inhomogeneous 3D-RISM-KH molecular theory of liquid interfaces and confined liquids, and will apply it to complex chemical and biomolecular problems, including: (i) drug discovery and transport across biomembranes and the blood-brain barrier for Alzheimer's and ALS therapeutics, (ii) prediction of cellulose nanocrystals (CNC) nanoparticles translocation across biomembranes towards nanotoxicity database, and (iii) nanoparticles in nanoporous carbon material for energy storage devices. The new methodological developments will be added to the existing implementations in the MOE (Canada) and ADF (Netherlands) software packages. Two PhD students will be involved and trained on this project.********