Intrinsically Multifunctional Energy Landscapes: A New Paradigm for Molecular Design

该项目旨在推进理论和计算机模拟，以了解和设计能够作为纳米设备发挥作用的分子。灵感来自最近对一种“内在无序”蛋白质的研究，这项研究为系统提出了新的设计原则，可以在不同的配置之间以受控的方式进行切换。基本的理论框架是基于对势能图景的分析，势能图景定义了任何分子或凝聚态系统的势能随粒子位置的变化。特别地，我们根据能量景观上的局部极小值以及连接它们的过渡态和路径来表示可观测的性质。在一组定义良好的近似中，该视图将相应的计算框架主要归结为几何优化。利用统计力学和单分子速率理论的工具将结果转化为实验可观测值。这些应用将涉及两个优先领域：功能材料的纳米级设计，以及对生物过程的理解。在以前的工作中，我们已经建立了具有自组织特性的系统与漏斗势能景观相关联，其中构型被引导向目标形态下坡。这一范例建立了一个普适性类，包括魔数簇(如巴克明斯特富勒烯)、结晶、自组装和蛋白质折叠。认识到本质上无序的蛋白质定义了另一类行为，这让我们考虑一种多功能系统的新范式。本提案中提出的研究假设是，多功能分子与多漏斗能量景观有关。了解自然存在的系统如何利用这种能力，例如结合不同的配体，将为可在不同结构之间切换的人造纳米设备提供设计原则。项目目标将通过一系列工作包实现：(1)方法学上的最新进展将被利用来获得实验时间和长度的尺度。在图形处理单元上实现相应的计算机程序可以提供超过两个数量级的效率增益。将实施和测试各种进一步转变抽样的新想法。(2)本质上无序的蛋白质可以通过结合不同的伴侣来执行多种细胞功能。我们的目标是检验这样一个假设，即多个函数与本质上的多漏斗势能格局相关联。结合伙伴对景观结构的聚焦效应将针对两种特定的蛋白质进行检查。(3)抗体在有抗原存在的情况下的特异性的演变将根据潜在的景观进行分析。结构预测以及抗原结合和连续突变的影响将与动态变化有关。(4)将对多漏斗景观进行核酸调查。G-四链结构之间的竞争预计会导致被高势垒分隔的不同形态，这可能是药物发现的重要目标。对于含有快速折叠片段的结构，将推导出基于DNA的超响应性器件的设计原则。(5)上述项目中获得的见解将用于设计人造纳米器件。在这里，我们将考虑通过外部条件(如外加磁场)和内部自由度(可通过实验获得)进行切换。例如，基于螺旋倒置的设备具有耦合直线运动和旋转运动的潜力。为了开发这种可能性，我们将设计一种可光开关的手性配体。DNA的B型和Z型之间的转换也可以提供一条通往纳米级开关的途径。

This project aims to advance theory and computer simulation to understand and design molecules capable of functioning as nanoscale devices. The inspiration comes from a recent study of an "intrinsically disordered" protein, which suggests new design principles for systems that can be switched in a controlled fashion between alternative configurations. The underlying theoretical framework is based on analysis of the potential energy landscape, which defines the variation of potential energy with particle positions for any molecular or condensed matter system. In particular, we formulate observable properties in terms of local minima on the energy landscape, and the transition states and pathways that connect them. Within a well-defined set of approximations, this view reduces the corresponding computational framework largely to geometry optimisation. The results are translated into experimental observables using the tools of statistical mechanics and unimolecular rate theory. The applications will address two Priority Areas: nanoscale design of functional materials, and understanding of biological processes. In previous work, we have established that systems with self-organising properties are associated with funnelled potential energy landscapes, where configurations are guided downhill towards a target morphology. This paradigm establishes a universality class, which includes magic number clusters (such as buckminsterfullerene), crystallisation, self-assembly, and protein folding. The realisation that intrinsically disordered proteins define an alternative class of behaviour leads us to consider a new paradigm for multifunctional systems. The research hypothesis addressed in the present proposal is that multifunctional molecules are associated with multifunnel energy landscapes. Understanding how naturally occurring systems exploit this capability, for example to bind different ligands, will provide design principles for artificial nanodevices that are switchable between alternative structures.Project goals will be achieved through a series of work packages:(1) Recent advances in methodology will be exploited to access experimental time and length scales. Implementing the corresponding computer programs on graphics processing units can provide efficiency gains exceeding two orders of magnitude. A variety of new ideas to further transform the sampling will be implemented and tested. (2) Intrinsically disordered proteins can perform multiple cellular functions by binding different partners. We aim to test the hypothesis that multiple functions are associated with an intrinsically multifunnel potential energy landscape. The focussing effect of binding partners on the structure of the landscape will be examined for two particular proteins.(3) The evolution of specificity for antibodies in the presence of antigens will be analysed in terms of the underlying landscape. Structure prediction and the effect of antigen binding and successive mutation will be related to changes in dynamics.(4) Multifunnel landscapes will be investigated for nucleic acids. Competition between G-quadruplex structures is predicted to result in alternative morphologies separated by high barriers, which may represent important targets for drug discovery. Design principles for ultraresponsive DNA-based devices will be deduced for structures that incorporate fast-folding segments.(5) The insight gained in the above projects will be used to design artificial nanodevices. Here we will consider switching via both external conditions, such as applied fields, and internal degrees of freedom that are accessible experimentally. For example, devices based upon helix inversion have the potential to couple linear and rotatory motion. To exploit this possibility we will design a photoswitchable chiral ligand. Transitions between the B and Z forms of DNA can also provide a route to nanoscale switches.