Understanding biomolecular association from large-scale first principles quantum mechanical simulations

从大规模第一原理量子力学模拟中理解生物分子关联

• 批准号: BB/I015922/1
• 金额: $ 11.71万
• 依托单位: University of Southampton
• 依托单位国家: 英国
• 项目类别: Training Grant
• 财政年份: 2011
• 资助国家: 英国
• 起止时间: 2011 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FI015922%2F1
• 关键词: Understanding; biomolecular; association; large; scale

Intermolecular association underpins most biological processes, such as the complex interactions between DNA and proteins during cell division in healthy cells but also in diseases such as cancers, or the apparently irreversible assembly of amyloid proteins in Alzheimer's and other age-related diseases. As a consequence, major research effort is targeted towards understanding and controlling biomolecular association, including developing drugs that will prevent or cure pathologies. The aim is to make the 'health span' as long as the ever increasing life span and achieve 'lifelong health and well-being', a strategic research priority of the BBSRC. Nevertheless, we are still often not able to predict biomolecular association with accuracy relevant to real applications. The point is that biomolecular interactions are determined by the electronic rearrangements that take place upon association (e.g. charge transfer and polarisation) which vary in strength, but not taken well into account by the force field approaches that are usually employed, with parameters tuned to particular situations. Quantum mechanical calculations from first principles ('ab initio') overcome these limitations as they include the electrons explicitly; however they have steep (cubic) computational scaling with system size and cannot be used in molecules with more than a few hundred atoms. The ONETEP program, developed by Dr Skylaris and his collaborators, is able to overcome this limitation as it is based on a novel reformulation of quantum theory which scales linearly with the number of atoms without loss of accuracy. We have performed calculations with ONETEP on systems with up to 50,000 atoms. The aim of this project, which will be supported by Boehringer Ingelheim (BI), is to overcome the shortcomings of force fields by using quantum calculations to treat the entire system, unlike previous attempts where only a small part of the system has been quantum. Since October 2008 BI have supported a PhD student through the BBSRC ICS scheme who has made the first steps towards this goal by showing that in certain well-known proteins a quantum description of the whole system can be essential as it leads to significant improvements in free energies of binding when compared to the same simulation protocol with force fields. Encouraged by these early successes, we want to apply this approach on more challenging pharmaceutical systems, together with new tools that are coming out as the functionality of ONETEP is currently enhanced by 3 postdoctoral researchers working in Southampton, Cambridge and Imperial College London. These new tools will include an implicit solvation model directly within the self-consistent quantum calculation, more accurate van der Waals interactions, and techniques for large-scale ab initio molecular dynamics simulations with direct calculation of free energies of binding. A parallel strand of the work will employ the multiple thermodynamic cycles approach of workers such Arieh Warshel (USC), Adrial Mulholland (Bristol) and Jonathan Essex (Southampton, with whom we collaborate) whereby 'classical' and 'quantum' systems are considered as different thermodynamic states and rigorous approaches for free energy changes (e.g. free energy perturbation theory) are used to make the transition between these states, using statistical acceptance tests to ensure that each 'move' is valid. For the first time we will apply such approaches by having the 'quantum' be the entire system, rather than a small portion of it, thus having a consistent representation. It has been a great pleasure so far to work with BBSRC and BI as it has enabled us to make the first steps in evaluating new and potentially very powerful simulation technologies. Our continued collaboration will ensure impact of direct relevance to the pharmaceutical industry which could move well outside the biomolecular association domain all the way to systems biology.

分子间的关联是大多数生物学过程的基础，例如在健康细胞的细胞分裂过程中DNA和蛋白质之间的复杂相互作用，以及在癌症等疾病中，或者在阿尔茨海默氏症和其他与年龄有关的疾病中淀粉样蛋白的明显不可逆的组装。因此，主要的研究工作是针对理解和控制生物分子的关联，包括开发药物，将预防或治愈病理。其目的是使“健康寿命”与不断增长的寿命一样长，实现“终身健康和福祉”，这是BBSRC的战略研究重点。尽管如此，我们仍然经常不能预测生物分子的关联与真实的应用相关的准确性。关键在于，生物分子相互作用是由缔合时发生的电子重排（例如电荷转移和极化）决定的，这些电子重排的强度不同，但通常采用的力场方法并没有很好地考虑到这一点，而参数则根据特定情况进行调整。第一原理的量子力学计算克服了这些限制，因为它们明确地包括了电子;然而，它们具有陡峭的（立方）计算尺度与系统尺寸，并且不能用于具有超过几百个原子的分子。由Skylaris博士和他的合作者开发的ONETEP程序能够克服这一限制，因为它是基于量子理论的一种新的重新表述，该理论与原子数量呈线性关系，而不会损失准确性。我们已经用ONETEP对多达50，000个原子的系统进行了计算。该项目将得到勃林格殷格翰（BI）的支持，其目的是通过使用量子计算来处理整个系统来克服力场的缺点，而不是像以前那样只对系统的一小部分进行量子计算。自2008年10月以来，BI已经通过BBSRC ICS计划支持了一名博士生，该计划已经朝着这一目标迈出了第一步，表明在某些众所周知的蛋白质中，整个系统的量子描述可能是必不可少的，因为与力场的相同模拟协议相比，它导致结合自由能的显着改善。受到这些早期成功的鼓舞，我们希望将这种方法应用于更具挑战性的制药系统，以及随着ONETEP功能的出现而出现的新工具，这些新工具目前由南安普顿，剑桥和帝国理工学院伦敦的3名博士后研究人员进行增强。这些新工具将包括直接在自洽量子计算中的隐式溶剂化模型，更精确的货车德瓦尔斯相互作用，以及直接计算结合自由能的大规模从头算分子动力学模拟技术。一个平行的工作链将采用多个热力学循环的方法，如阿里耶沃谢尔（南加州大学），阿德里亚穆赫兰（布里斯托）和乔纳森埃塞克斯的工人（南安普顿，与我们合作），其中“经典”和“量子”系统被认为是不同的热力学状态和严格的方法，自由能的变化（例如自由能微扰理论）用于在这些状态之间进行转换，使用统计验收测试来确保每个“移动”是有效的。这是我们第一次应用这种方法，让“量子”成为整个系统，而不是它的一小部分，从而具有一致的表示。到目前为止，与BBSRC和BI合作是一件非常愉快的事情，因为它使我们能够在评估新的和潜在的非常强大的仿真技术方面迈出第一步。我们的持续合作将确保与制药行业直接相关的影响，这可能会远远超出生物分子缔合领域，一直到系统生物学。