Multiscale Modeling of Protein Mediated Membrane Phase and Dynamical Behavior

项目编号：CBET: 0730955项目负责人：Ravi radhakrishna大学/机构：宾夕法尼亚大学标题：蛋白质介导膜相和动力学行为的多尺度建模纳米生物技术中的几个设计问题是由多个长度和时间尺度的基本过程的复杂相互作用所控制的。虽然通过实验方法对这些过程进行连贯和完整的描述并不总是可能的，但通过多尺度建模方法，建模和模拟方法可以在原子、中尺度和宏观尺度分辨率上提供有价值的见解。该项目致力于实现与一类具有纳米级包裹体的复杂流体相关的平衡和动态过程的多尺度描述，即由膜结合蛋白和膜结合蛋白介导的生物膜。主要目标是开发一种多尺度技术，并将其应用于实现定量和实验可测试的描述，即分子水平上的相互作用如何导致介观水平上的特性表现（接近与生物细胞相关的长度和时间尺度）。智力优势：方法进步的核心是提出了一种整合两种不同现象学方法的新策略，即膜动力学的场论（连续体）描述和蛋白质动力学的离散（晶格）描述，这种组合产生了一种新的计算技术，具有描述涉及多个空间和时间尺度的复杂过程中的动态行为的能力。KMC-TDGL算法是独特和创新的，它能够结合两种不同的现象学形式（动力学蒙特卡罗和时间相关的金兹堡朗道），以这种方式允许两种方法之间的双向耦合。结合的方法将被应用于获得曲率诱导蛋白如何介导细胞膜动力学的统一图像。该方法将在两个层面进行验证。(1)通过原子水平的分子动力学模拟验证和参数化纳米尺度下相互作用的现象学势。(2) KMC-TDGL模拟也将通过直接将预测与具有良好特征的实验进行比较来进行批判性评估。这将使所提出的统一方法建立在原子水平相互作用的基础上，同时保留了在介观水平上描述动力学和热力学性质的能力。待开发的多尺度方法具有通用性，适用于多种生物物理和生化过程，如发生在细胞膜上的蛋白质介导的生物现象。这些包括由蛋白质-蛋白质相互作用介导的生物粘附、内吞作用（蛋白质或纳米载体的内化机制）、筏形形成（脂质双层阶段富含胆固醇的微结构域）或小泡的生物发生（在膜中形成的瓶状囊泡结构）。更广泛的影响：该方法也可推广到膜生物物理学以外的过程，如DNA动力学，晶体生长动力学等。因此，它可能会对制药科学、合成生物学、纳米生物技术和系统生物学等学科中纳米生物界面的基础科学发现产生重大影响。作为工程和定量生物学跨学科研究项目的补充，拟议的教育和推广项目将利用宾夕法尼亚大学现有的渠道，并引入新的途径，建立一个严谨而有远见的综合项目，包括理论、计算和实验技术。该研究项目不仅将通过PI的研究和教学活动对一些研究生和本科生产生直接影响，而且还将通过拟议的活动进行传播和国际合作，对国内外的学术学者产生直接影响，并赋予强大的科技价值。

Proposal Number: CBET: 0730955 Principal Investigator: Ravi RadhakrishnaUniversity/Institution: University of PennsylvaniaTitle: Multiscale Modeling of Protein Mediated Membrane Phase and Dynamical BehaviorSeveral design problems in nano-bio-technology are governed by a complex interplay of fundamental processes at multiple length and timescales. While a coherent and complete description of these processes is not always possible by experimental methods, modeling and simulation approaches can provide valuable insights at atomic, mesoscale, and macroscale resolutions through multiscale modeling approaches. This project strives to achieve a multiscale description of equilibrium and dynamic processes associated with a class of complex fluids with nanoscale inclusions, namely, biological membranes mediated by membrane associating and membrane bound proteins. The primary objective is to develop a multiscale technology and apply it to achieve a quantitative and experimentally testable description how interactions at a molecular level lead to manifestation of properties at the mesoscopic level (approaching the length and timescales relevant to a biological cell). Intellectual Merit: At the core of the methodological advance is the proposal to devise a new strategy for integrating two different phenomenological approaches, namely, a field theoretic (continuum) description for the membrane dynamics and a discrete (lattice) description for the protein dynamics, a combination that results in a new computational technology with the power to describe dynamical behavior in complex processes involving multiple spatial and temporal scales. The KMC-TDGL algorithm is unique and innovative in its ability to combine two disparate phenomenological formalisms (Kinetic Monte Carlo and Time Dependent Ginzburg Landau) in such a manner as to allow for a two-way coupling between the two methods. The combined approach will be applied to obtain a unified picture of how curvature inducing proteins mediate cell membrane dynamics. The method will be validated at two levels. (1) Phenomenological potentials of interaction at the nanoscopic scale will be validated and parameterized by atomic-level molecular dynamics simulations. (2) The KMC-TDGL simulations will also be critically evaluated by comparing the predictions directly with well-characterized experiments. This will enable the proposed unified approach to be founded on the basis of atomic level interactions while retaining the capability of describing dynamical and thermodynamic properties at the mesoscopic level. The multiscale approach to be developed is generalizable and applicable to a variety of biophysical and biochemical processes such as protein-mediated biological phenomena occurring on the cell membrane. These include biological adhesion mediated by protein-protein interaction, endocytosis (internalization mechanism for proteins or nanocarriers), raft formation (microdomains in the lipid bilayer phase that are enriched in cholesterol), or biogenesis of caveolae (flask shaped vesicular structures formed in the membranes). Broader Impact: The approach is also generalizable to processes outside of membrane biophysics such as DNA dynamics, crystal growth kinetics etc. Therefore, it is likely to have a significant impact in enabling fundamental scientific discoveries at the nanobio interface in the disciplines of pharmaceutical science, synthetic biology, nano-bio-technology, and systems biology. Complementing the interdisciplinary research program in engineering and quantitative biology, the proposed educational and outreach programs will leverage existing channels at the University of Pennsylvania, as well as introduce new avenues to build a rigorous and visionary integrated program encompassing theoretical, computational, and experimental technologies. The research program will also provide direct impact and impart strong scientific and technological value not only to several graduate students and undergraduate students through the research and teaching activities of the PI, but also to academic scholars nationally and internationally through the proposed activities for dissemination and international collaboration.