Multiscale Modeling of Protein Mediated Membrane Phase and Dynamical Behavior

建议编号：CBET：0730955首席研究员：Ravi Radhakrishna大学/机构：宾夕法尼亚大学标题：蛋白质介导膜相和动态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决定的。虽然实验方法并不总是能够对这些过程进行连贯和完整的描述，但建模和模拟方法可以通过多尺度建模方法在原子、中尺度和宏观尺度上提供有价值的见解。本项目致力于实现对一类具有纳米级包裹体的复杂流体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，并应用它来实现定量和可实验测试的描述，描述分子水平上的相互作用如何导致介观水平上的性质表现(接近与生物细胞相关的长度和时间尺度)。智力优势：方法论进步的核心是提出了一种新的策略来整合两种不同的现象学方法，即对膜动力学的场论(连续)描述和对蛋白质动力学的离散(晶格)描述，这种结合导致了一种新的计算技术，该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力学行为的能力。KMC-TDGL算法的独特和创新之处在于，它能够结合两种不同的现象学形式(动力学蒙特卡罗和依赖时间的金兹堡朗道)，从而允许两种方法之间的双向耦合。这一结合的方法将被应用于获得曲率诱导蛋白如何调节细胞膜动力学的统一图像。该方法将在两个层面上进行验证。(1)纳米尺度上的唯象相互作用势将通过原子水平的分子动力学模拟来验证和参数化。(2)KMC-TDGL模拟也将通过直接将预测与特征良好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，同时保留在介观水平上描述动力学和热力学性质的能力。将要开发的多尺度方法是可推广的，并适用于各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、内吞作用(蛋白质或纳米载体的内化机制)、RAFT形成(脂质双层相中富含胆固醇的微区)或小窝(在膜中形成的瓶状泡状结构)的生物发生所介导的生物黏附。更广泛的影响：该方法也可推广到膜生物物理以外的过程，如DNA动力学、晶体生长动力学等。因此，它可能对制药科学、合成生物学、纳米生物技术和系统生物学学科中的纳米生物界面的基础科学发现产生重大影响。作为工程学和数量生物学跨学科研究计划的补充，拟议的教育和推广计划将利用宾夕法尼亚大学现有的渠道，并引入新的途径，以建立一个包括理论、计算和实验技术的严谨和有远见的综合计划。该研究计划还将通过国际和平研究所的研究和教学活动，不仅对几名研究生和本科生，而且通过拟议的传播和国际合作活动，向国内和国际学者提供直接影响和传授强大的科学技术价值。

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.