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

拟议研究计划的首要主题是开发和应用建模方法来理解膜蛋白和纳米孔中溶质在多个时间和空间尺度上的运输。在过去的五年中，我们在改善金属蛋白的极化模型，开发复杂生物分子系统中自由能采样的新方法或扩展直接结合实验限制方面取得了重大进展。我们的实验室开发了基于纳米孔和膜蛋白的粗粒度、原子、极化和QM/MM模型的蒙特卡罗分子动力学模拟方法。我们将在进一步扩大我们的研究项目的两个主要方向。第一个目标是扩展已开发的方法，以了解膜孔运输功能与环境效应（如质子化，温度或膜组分对特定运输的影响）之间的密切相互关系。非均匀介质环境中质子/离子/溶质输运和极化效应的精确描述是众所周知的开放问题，也是膜输运领域最受欢迎的问题之一。我们将扩展先前开发的采样技术，改进的原子模型，极化力场或QM/MM方法，以研究环境对质子线或模型溶剂中传输模式的影响，以研究阴离子选择性转运体的溶质特异性。第二个研究方向是基于时空尺度对纳米孔输运控制的根本性挑战。生物纳米孔在核酸或蛋白质测序方面具有多种潜在的应用前景。然而，这些系统中货物（溶质）诱导门控的分子起源是未知的，但仍然是信号分辨率的混淆因素之一。建模工作将允许在不同时间尺度/分辨率下的前沿模拟数据/分析和对两个已建立的纳米孔的实验研究的前瞻性结合，并应用于传感。这两个方向是密切相关的，因为理解纳米输运和连接各种时间和空间尺度的挑战是现代物理化学的一个基本问题的另一种表现-如何明确地重建凝聚态过程的自由能，然后解决纳米输运的热力学和动力学之间的相互联系。所提出的工作将加强物理化学与生物结构之间的联系，并实现对自然世界现象的更严格的方法。该计划还将改进理论和方法，解决表面化学领域的基本问题，合理设计具有编程特性的传感器和执行器，以及膜运输的生物化学。

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.