Coarse-Grained Modelling of DNA-Protein Interactions

DNA-蛋白质相互作用的粗粒度建模

• 批准号: 2888934
• 金额: --
• 依托单位: University of Strathclyde
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2888934
• 关键词: Coarse; Grained; Modelling; DNA; Protein

Proteins perform a vast array of essential biological functions within every living organism. In the context of the cell, they do not perform their function as individual entities, but in complexes with other biomacromolecules. Consequently, the focus of modern structural genomics is rapidly shifting toward the study of macromolecular DNA-protein complexes, which are at the origin of many infectious diseases, genetic disorders, and cancer.While established experimental high-resolution techniques like small-angle X-ray scattering (SAXS) provide a static view of DNA-protein complexes, computer simulations are often the only tool capable of providing key dynamic information of how these complexes perform their functions. Coarse-grained (CG) models, which reproduce the relevant structural features and thermodynamic properties at greatly reduced computational costs play here a particularly important role. As biology is known for having the largest and most complex structures in nature, CG models are not only an efficient alternative to atomistic approaches. They are indispensable for modelling biomacromolecules such as long DNA strands and large proteins on timescales in the millisecond range and beyond.During the last decade striking progress has been made in each separate field, CG modelling of DNA on one side, and CG modelling of proteins on the other side. The oxDNA model [1] (see Methodology) has emerged as the leading CG model of DNA and RNA. Similarly, the Associative Memory, Water-Mediated, Structure and Energy Model (AWSEM, see Methodology) is among the most successful CG protein models to date. Both models are implemented in the Large-scale Atomic/Molecular Massively Parallel Simulator [2 - 4] (LAMMPS, see Methodology), a global community molecular dynamics code, but cannot be used in conjunction. This leaves the emerging field of DNA-protein interactions inaccessible, which is in principle much broader than DNA and proteins alone.This project will develop both the theoretical concepts and software implementations of a coupling of the oxDNA and AWSEM models. Through the combined use of the two individually forthcoming models and the produced software it will constitute a transformative step in the emerging field of CG modelling of DNA-protein interactions, enable simulations on very long time and large length scales, and bring together growing scientific communities in structural biology, DNA and protein modelling, synthetic biology and nanotechnology. The new functionality will be directly applied to projects related to antimicrobial resistance and DNA nanotechnology.

蛋白质在每个生物体中都具有大量必不可少的生物学功能。在细胞的背景下，它们不作为单个实体的功能，而是在与其他生物大分子的复合物中执行其功能。 Consequently, the focus of modern structural genomics is rapidly shifting toward the study of macromolecular DNA-protein complexes, which are at the origin of many infectious diseases, genetic disorders, and cancer.While established experimental high-resolution techniques like small-angle X-ray scattering (SAXS) provide a static view of DNA-protein complexes, computer simulations are often the only tool capable of providing key dynamic information of这些复合物如何执行其功能。粗粒（CG）模型，该模型在这里大大降低了相关的结构特征和热力学特性在这里起着特别重要的作用。由于生物学以具有本质上最大，最复杂的结构而闻名，因此CG模型不仅是原子方法的有效替代方法。它们对于对生物乳粒分子进行建模是必不可少的，例如在毫秒范围及其他地区的时标上的长DNA链和大蛋白。在过去的十年中，在每个单独的领域都取得了惊人的进度，一侧的DNA建模以及另一侧的CG建模。 OxDNA模型[1]（参见方法论）已成为DNA和RNA的领先CG模型。同样，关联记忆，水介导的结构和能量模型（AWSEM，请参阅方法论）是迄今为止最成功的CG蛋白质模型之一。这两种模型均在大规模的原子/分子大量平行模拟器中实现[2-4]（lammps，请参阅方法论），这是一种全球社区分子动力学代码，但不能用于结合。这使DNA-蛋白质相互作用的新兴领域无法访问，这在原则上比DNA和蛋白质更广泛。该项目将共同发展OxDNA和AWSEM模型的理论概念和软件实现。通过将两个单独的即将到来的模型的结合使用及其生产的软件，它将构成DNA-蛋白质相互作用的新兴领域的变革性步骤，启用长时间和大长度尺度的模拟，并在结构生物学，DNA和蛋白质建模，合成生物学和纳米学和纳米杂质学中汇总成不断发展的科学社区。新功能将直接应用于与抗菌耐药性和DNA纳米技术有关的项目。