NER: Simulation Strategies for Biomolecular Assembly of Nanoscale Building Blocks

首席研究员将开发一种模拟策略，该策略可用于阐明功能化纳米级构建块（nbb）使用生物分子作为nbb之间的“连接剂”或“连接器”组装成有序结构的基本原理。最近的开创性实验工作表明，适当功能化的nbb可以使用生物或合成大分子作为连接剂组装成具有特定性质和功能的简单有序结构。例如，由DNA、生物素或合成聚合物功能化的纳米级金颗粒大小在2纳米至30纳米之间，已被证明可以组装成三维六联体紧密排列的结构和延伸数百至数千纳米的球体。DNA，本质上是一种“数字可编程”的生物分子，作为nbb的“组装者”尤其有趣，因为特定的连接子-连接子相互作用可以通过故意将定制的互补核苷酸序列插入不同的DNA链中来编程。然而，除了这些令人兴奋的“概念验证”研究之外，还没有关于NBB/大分子组装可能的合成和加工策略的系统知识，也没有可能的结构范围，甚至没有确定这些复杂系统的巨大参数空间的主轴。计算机模拟将有助于定义和有效地绘制参数空间，并为装配过程提供基本的见解。然而，尽管在计算能力和模拟算法方面取得了进步，但控制NBBs和溶液中大分子的分阶段、分层排序过程的不同时间和长度尺度禁止立即应用任何一种“现成的”模拟技术。在这个项目中，PI将探索几种结合不同已知的基于分子和/或粒子的模拟方法的想法，具体目标是克服nbb和大分子连接物移动的不同时间尺度。她将考虑单独和联合使用几种经典的分子或所谓的“基于粒子”的模拟方法，包括分子动力学、布朗动力学和离晶格蒙特卡罗，以便开发一种能够模拟NBB/生物分子组装的整体模拟策略，在计算限制的情况下，尽可能保持化学保真度。重点将是使用DNA作为组装体，但该策略通常也适用于其他大分子连接体。模拟方法将能够建模的NBB几何形状包括球体和多面体（例如金纳米颗粒，胶体二氧化硅，巴基球，纳米棱镜，CdSe量子点），纳米棒，纳米片（例如粘土）和纳米聚集体（例如线性链聚集体）。PI期望所提出的研究能为NBB的程序化大分子组装和DNA/NBB组装的建模能力提供重要和必要的进展。在这个为期一年的项目结束时，她将测试几种模拟dna组装纳米颗粒结构的策略，并设计一种综合的模拟方法，能够用经典的模拟技术模拟任意组成和几何形状的nbb组装，这些nbb由生物分子或任意化学结构的大分子连接。这种方法将为计算纳米科学领域的研究人员提供模拟策略，以支持纳米尺度系统的详细研究。如果没有这些策略，模拟科学可能无法对纳米级构建块的自我和引导组装的基本理解和设计原则做出重大贡献。

The Principal Investigator will develop a simulation strategy that can be used to elucidate the fundamental principles by which functionalized nanoscale building blocks (NBBs) are assembled into ordered structures using biomolecules as "linkers" or "connectors" between the NBBs. Recent pioneering experimental work has demonstrated that suitably functionalized NBBs can be assembled into rather simple ordered structures with specific properties and functionalities using biological or synthetic macromolecules as linkers. For example, nanoscopic gold particles ranging in size from 2 nm to 30 nm and functionalized by DNA, biotin, or synthetic polymers have been shown to assemble into three-dimensional hexatic close-packed structures and spheres extending over hundreds to thousands of nanometers. DNA, in essence a "digitally programmable" biomolecule, is especially intriguing as an "assembler" of NBBs because specific linker-linker interactions can be programmed by inserting purposely tailored complementary nucleotide sequences into different DNA strands.Aside from these exciting "proof-of-concept" studies, however, no systematic knowledge with regard to possible synthesis and processing strategies, nor the range of structures possible, for NBB/macromolecule assemblies has been obtained - not even the principal axes of the vast parameter space of these complex systems have been identified. Computer simulations will be instrumental in the effort to define and efficiently map out parameter space and provide fundamental insight to the assembly process. Despite advances in computational power and simulation algorithms, however, the disparate time and length scales that govern the staged, hierarchical ordering processes of NBBs and macromolecules in solution prohibit the immediate application of any one "off-the-shelf" simulation technique.In this project, the PI will explore several ideas for combining different well-known molecular and/or particle-based simulation methodologies with the specific aim of overcoming the disparate time scales on which the NBBs and macromolecule linkers move. She will consider the individual and combined use of several classical molecular or so-called "particle-based" simulation methods, including molecular dynamics, Brownian dynamics, and off-lattice Monte Carlo, in order to develop an overall simulation strategy capable of simulating NBB/biomolecule assemblies with as much chemical fidelity as possible given computational limitations. The focus will be on using DNA as assemblers, but the strategy will generally apply to other macromolecular linkers as well. NBB geometries that the simulation approach will be capable of modeling include spheres and polyhedra (e.g. gold nanoparticles, colloidal silica, Buckyballs, nanoprisms, CdSe quantum dots), nanorods, nanosheets (e.g. clays) and nanoaggregates (e.g. linear chain aggregates).The PI expects the proposed research to provide an important and necessary advance in the ability to model programmed macromolecular assembly of NBBs in general and DNA/NBB assemblies in particular. At the end of this one-year project, she will have tested several strategies for simulating DNA-assembled nanoparticle structures, and designed a comprehensive simulation methodology capable of modeling assemblies of NBBs of arbitrary composition and geometry joined by biomolecules or macromolecules of arbitrary chemical structure with classical simulation techniques. This methodology will provide researchers in the field of computational nanoscience with simulation strategies to support detailed investigations in nanoscale systems. Without these strategies, simulation science will likely be unable to contribute significantly to the quest for fundamental understanding and design principles for the self- and guided-assembly of nanoscale building blocks.