Hierarchical Modeling/Ion Channel and Receptor Mechanism

描述（由申请人提供）：正常发挥功能的膜蛋白对健康至关重要;它们的缺陷与许多已知的疾病状态有关。膜蛋白是许多代谢和毒理学活性物质的靶标，并且部分负责这些物质的摄取、代谢和清除。尽管膜蛋白的重要性，其高分辨率的结构和作用机制的知识远远落后于一般蛋白质的这些性质的知识。理论建模可能有助于破译膜蛋白的结构-功能关系，然而膜蛋白的理论建模也落后于球状蛋白的建模。我们的长期目标是在这个拟议的项目是膜蛋白的结构和功能的理论建模，以提供离子渗透和配体结合过程中的分子和原子事件如何导致通道电导和调节的介观事件的理解。在建模离子通道中的一个问题是表征它们的功能，即离子电流-电压关系，需要在至少微秒时间尺度上对过程进行建模，这对于当前蛋白质的原子模拟是不可访问的。因此，本申请的目的是创建和应用用于离子渗透通过开放通道的可靠但计算有效的分子水平模型，其考虑通道蛋白质分子结构、极化率和短时间尺度灵活性，但能够预测可观察到的离子电流（根据分子动力学标准，缓慢的过程）。为了有效地跨越广泛的时间尺度相关的离子渗透，所提出的模型是分层的性质。我们在这个项目中的目标是：开发，测试和应用分层算法，通过已知或预测的3D结构的开放灵活的通道来模拟离子流。为了实现这种分层的方法，我们将使用几个级别的分辨率（“粒化”）的系统正在考虑：从全原子分子建模的通道蛋白质与其周围的介质粗粒度连续近似模型，能够跨越较长的时间尺度和介观尺寸。使用这种分子/介观层次模型，我们将研究几个系统的医学和医学工程的兴趣。我们预计，该项目的结果将是重要的理论和计算方法来研究膜蛋白的未来方向，因为一旦基于蛋白质结构的功能模型已经开发出来，它将成为可能，通过合理的计算机辅助设计开发特定的理论方法来设计药物和药物输送系统的膜蛋白。

DESCRIPTION (provided by applicant): Membrane proteins that function normally are vital to health; their defects are associated with many known disease states. Membrane proteins are the targets of many pharmacologically and toxicologically active substances and are responsible, in part, for the uptake, metabolism, and clearance of these substances. Despite the importance of membrane proteins, knowledge of their high-resolution structures and mechanisms of action has lagged far behind the knowledge of these properties of proteins in general. Theoretical modeling may help in deciphering the structure-function relationship of membrane proteins, however theoretical modeling of membrane proteins also lags behind the modeling of globular proteins. Our long-term goal in this proposed project is theoretical modeling of structure and function of membrane proteins to provide understanding of how the molecular and atomistic events during ion permeation and ligand binding lead to mesoscopic events of channel conductance and regulation. One problem in modeling ion channels is that characterizing their function, i.e. ion current - voltage relationships, requires modeling of processes on at least the microsecond time-scale, inaccessible for current atomistic simulations of proteins. The objective of this application is thus to create and apply reliable yet computationally efficient molecular-level models for ion permeation through open channels, which take into account channel protein molecular structure, polarizability and short time-scale flexibility, yet are capable of predicting observable ion currents (a slow process by Molecular Dynamics standards). In order to efficiently span a wide range of time-scales relevant to the ion permeation, the proposed models are of hierarchical nature. Our aims in this project are: to develop, test and apply hierarchical algorithms to model ion currents through open flexible channels of known or predicted 3D structures. In order to implement this hierarchical approach we will use several levels of resolution ("graining") of the system under consideration: from all-atom molecular modeling of the channel protein with its surrounding medium to coarse grained continuum approximate models, capable of spanning longer time-scales and mesoscopic sizes. Using this molecular/mesoscopic hierarchy of models we will study several systems of medical and medical engineering interest. We expect that the outcome of this proposed project will be significant for future direction of theoretical and computational approaches to study membrane proteins because once a functional model based on protein structure has been developed it will become possible to develop specific theoretical methodologies for designing drugs and drug delivery systems for membrane proteins via rational computer-aided design.