Hierarchical Modeling/Ion Channel and Receptor Mechanism

描述(申请人提供)：正常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。膜蛋白是许多药理和毒理活性物质的靶标，并在一定程度上负责这些物质的吸收、代谢和清除。尽管膜蛋白很重要，但对其高分辨率结构和作用机制的了解远远落后于对蛋白质这些性质的了解。理论建模有助于破译膜蛋白的结构-功能关系，但膜蛋白的理论建模滞后于球状蛋白的建模。我们在这个拟议的项目中的长期目标是对膜蛋白的结构和功能进行理论建模，以了解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。离子通道建模的一个问题是，表征它们的功能，即离子电流-电压关系，需要至少在微秒时间尺度上对过程进行建模，这对于目前的蛋白质原子模拟是无法实现的。因此，这项应用的目标是创建和应用可靠但计算高效的分子水平的离子通过开放通道的渗透模型，该模型考虑到通道蛋白质的分子结构、极化率和短时间尺度的灵活性，但能够预测可观察到的离子电流(按分子动力学标准是一个缓慢的过程)。为了有效地跨越与离子渗透相关的大范围的时间尺度，所提出的模型具有层次化性质。我们在这个项目中的目标是：开发、测试和应用分层算法来模拟通过已知或预测的3D结构的开放灵活通道的离子电流。为了实现这种分层方法，我们将使用所考虑系统的几个级别的分辨率(“颗粒化”)：从通道蛋白及其周围介质的全原子分子建模到能够跨越更长时间尺度和介观尺寸的粗粒度连续统近似模型。使用这个分子/介观层次模型，我们将研究几个医学和医学工程感兴趣的系统。我们希望这一项目的结果将对未来膜蛋白的理论和计算方法的发展方向具有重要意义，因为一旦基于蛋白质结构的功能模型被开发出来，就有可能通过合理的计算机辅助设计来开发针对膜蛋白的药物和药物释放系统的具体理论方法。

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.