Core--Development of new Features in MCell

典型的细胞过程发生在高度组织化的亚细胞空间，在那里配体和配体结合分子参与复杂的信号通路。因此，一般而言，仅用混合良好的全细胞来考虑分子信号是不够的，例如细胞内钙离子浓度，而必须关注相关的亚细胞微域。信号和效应器分子的数量可以相当少，计算机已经变得足够强大，现在可以在亚细胞区域模拟每一个重要的分子。Mcell是一个通用的计算机程序，旨在模拟微域和相关的生化信号机制。的具体目标 这一核心将为Mcell增加新的能力，将分子和大分子复合体的映射过程简化为细胞超微结构的真实三维重建，并将实施模拟扩散分子之间相互作用的算法。第一个具体目标是设计算法，允许模拟扩散分子之间所有可能的成对相互作用，这将允许模拟Mceli内的胞质信号转导级联。第二个具体目标是开发一种用户友好的蜂窝计算机辅助设计(CAD)系统，用于Mcell计划。细胞CAD系统将允许以图形方式设计神经元和其他类型细胞的真实模型 在亚细胞和分子水平，并以特定密度在表面快速填充通道、泵和其他分子。第三个具体目标是设计算法来简化大分子络合物和反应网络的表示。这将涉及开发一种用于反应网络的高级和分层表示语言，该语言将为表示复杂的反应网络提供方便的、机器可读的速记。这一提议的Mcell开发还将允许用户通过根据特定应用需要定义指定反应物内部状态的标签结构来指定粗粒化水平。Mcell的这些新建模功能包括 这是项目1(Sejnowski)和项目3(Kennedy)成功的先决条件，并将促进将项目2(Weinberg)和项目4(Svoboda)的实验数据整合到Mcell模拟中。

Typical cellular processes occur in highly organized subcellular spaces, where ligand and ligand-binding molecules participate in complex signaling pathways. In general, then, it is not sufficient to consider molecular signals, such as the intracellular Ca 2+ concentration, only in well-mixed whole cell terms, but instead attention must center on the relevant subcellular microdomains. The number of signaling and effector molecules can be quite small, and computers have become powerful enough so that it is now feasible to simulate every important molecule in subcellular regions. MCell is a general computer program designed to simulate microdomains and associated biochemical signaling mechanisms. The specific aims of this core will add new capabilities to MCell that will streamline the process of mapping molecules and macromolecular complexes into realistic three-dimensional reconstructions of cellular ultrastructure and will implement algorithms for simulating interactions between diffusing molecules. The first specific aim is to design algorithms to permit simulation of all possible pair-wise interactions between diffusing molecules, which will allow simulation of cytosolic signal transduction cascades within MCelI. The second specific aim is to develop a user-friendly cellular computer-assisted design (CAD) system for use with the MCell program. The cellular CAD system will allow graphical design of realistic models of neurons and other cell types at the subcellular and molecular level and to rapidly populate surfaces with channels, pumps and other molecules at specified densities. The third specific aim is to design algorithms to streamline the representation of macromolecular complexes and reaction networks. This will involve the development of a high-level and hierarchical representation language for reaction networks that will provide a convenient, machine readable, shorthand for representing complex reaction networks. This proposed MCell development will also allow the user to specify the level of coarse-graining by letting the label structure specifying the internal states of reactants to be defined as needed for specific applications. These new modeling capabilities for MCell are prerequisite for the success of Project 1 (Sejnowski) and Project 3 (Kennedy) in this proposal and will facilitate the integration of experimental data from Project 2 (Weinberg) and Project 4 (Svoboda) into MCell simulations.