Multiscale Modeling of Protein Mediated Membrane Phase and Dynamical Behavior

提案编号：CBET：0730955首席研究员：拉维Radhakrishna大学/机构：宾夕法尼亚大学标题：蛋白质介导的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一个复杂的相互作用的基本过程在多个长度和时间尺度。虽然这些过程的连贯和完整的描述并不总是可能的实验方法，建模和模拟方法可以提供有价值的见解，在原子，中尺度和宏观尺度的分辨率，通过多尺度建模方法。该项目致力于实现与一类具有纳米级内含物的复杂流体相关的平衡和动态过程的多尺度描述，即由膜缔合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，并应用它来实现一个定量和实验可测试的描述如何在分子水平上的相互作用导致在介观水平上的性能表现（接近生物细胞相关的长度和时间尺度）。智力优势：在方法论的进步的核心是建议设计一个新的战略，整合两种不同的现象学方法，即，一个场论（连续）描述的膜动力学和离散（晶格）描述的蛋白质动力学，一个组合，结果在一个新的计算技术的权力，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KMC-TDGL算法是独特的和创新的，它的能力，联合收割机两个不同的现象学形式主义（动力学蒙特卡罗和时间依赖金兹伯格朗道）在这样一种方式，以允许两种方法之间的双向耦合。结合的方法将适用于获得一个统一的图片曲率诱导蛋白质如何介导细胞膜动力学。该方法将在两个水平上进行验证。(1)在纳米尺度上的相互作用的现象学势将通过原子级分子动力学模拟进行验证和参数化。(2)KMC-TDGL模拟也将通过直接将预测与表征良好的实验进行比较来进行严格评估。这将使所提出的统一方法建立在原子水平的相互作用的基础上，同时保留在介观水平上描述动力学和热力学性质的能力。要开发的多尺度方法是可推广的，适用于各种生物物理和生物化学过程，如蛋白质介导的生物现象发生在细胞膜上。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）、筏形成（脂质双层相中富含胆固醇的微区）或小窝的生物发生（在膜中形成的烧瓶状囊泡结构）。更广泛的影响：该方法也是可推广的过程以外的膜生物物理学，如DNA动力学，晶体生长动力学等，因此，它可能会有重大影响，使基础科学发现在纳米生物接口的学科，制药科学，合成生物学，纳米生物技术，系统生物学。为了补充工程和定量生物学的跨学科研究计划，拟议的教育和推广计划将利用宾夕法尼亚大学的现有渠道，并引入新的途径来建立一个严格和有远见的综合计划，包括理论，计算和实验技术。该研究计划还将提供直接的影响，并通过PI的研究和教学活动，不仅向几名研究生和本科生传授强大的科学和技术价值，还将通过拟议的传播和国际合作活动向国内和国际上的学术学者传授。

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.