Multi-scale models of solute and ion transport in membrane proteins and artificial nanopores

点击翻译按钮获取中文摘要

The overarching theme of the proposed research program is the development and application of modelling approaches to understanding of solute transport in membrane proteins and nanopores across multiple temporal and spatial scales. In the past five years we have made significant progress in improving polarizable models for metalloproteins, developing novel methods for free energy sampling in complex biomolecular systems or expanding with direct incorporation for experimental constraints. Our lab developed methods for Monte-Carlo, Molecular Dynamics simulations based on coarse-grained, atomistic, polarizable and QM/MM models of nanopores and membrane proteins. We will pursue two major directions in further expansion of our research project.    The first aim is to expand developed methods to understand an intimate inter-relationship between membrane pore transport function and environmental effects such as protonation, impact of temperature or membrane components on the specific transport). The accurate description of proton/ion/solute transport and polarization effects in non-homogenous dielectric environment are well-known open problems and are among the most sought-after in the area of membrane transport. We will expand previously developed sampling techniques, improved atomistic models, polarizable force-fields or QM/MM methods to investigate impact of the environment on transport mode in proton wires or model solvents to investigations of solute specificity in anion-selective transporters.    The second research direction is driven by the fundamental challenges in relating spatial and temporal scales in control of nanopore transport. Biological nanopores have multiple potential applications in nucleic acid or protein sequencing. However, molecular origins of cargo(solute)-induced gating in these systems are unknown but remain one of the confounding factors for signal resolution. The modelling efforts will allow a prospective combination of the cutting-edge simulation data/analysis at different time scales/resolution and experimental studies on two established nanopores with applications to sensing.    These two directions are closely interrelated as the challenges in understanding nano-transport and linking various temporal are spatial scales are yet another manifestation for one of the fundamental question in modern physical chemistry - how to unambiguously reconstruct free energy of the process in the condensed phase and then resolve inter-connection between thermodynamics and kinetics of nano-transport. The proposed work will strengthen the connections between physical chemistry and biological structure and achieve more rigorous approach to the phenomena of the natural world. The program will also result in improved theories and methods addressing fundamental problems in the area of surface chemistry, rational design of sensors and actuators with programmed properties and biochemistry of membrane transport.