AMBER force field consortium: a coherent biomolecular simulation platform

描述(申请人提供)：分子模拟在生化和生物物理科学中发挥了重要作用。已经取得的进展使得对日益复杂的系统进行广泛的模拟成为可能。为了进一步推动这些进展，这组研究人员建议成立一个联盟来开发参数和模拟方法，这些参数和模拟方法是分子模拟平台基础的一部分。拟议中的联合体将一群年轻的研究人员聚集在一起，他们都是加州大学旧金山分校科尔曼实验室的前成员，以推动“琥珀”部队领域的努力达到新的水平。这些研究人员作出了重大贡献：o开发琥珀模拟包和力场参数，并在过去开展了重大合作，这从作者之间的许多联合出版物中可见一斑。这一建议的一个关键重点是不仅要为蛋白质、核酸和类药物分子建立通用、可靠和广泛适用的力场，而且要通过与其他现有方法和力场的彻底测试和比较来验证这些力场。目前，根据模型(极化、电荷模型、溶剂表示)的选择仍然是活跃的研究问题。这项提议影响广泛，因为将研究多种方法，从开发下一代通用可极化力场到专门设计的利用连续介质溶剂的模型。从组建的团队来看，显然在蛋白质和核酸模拟方面有相当多的专业知识，这将有助于指导努力向前推进。该联盟的一个关键目标是进一步加强密切合作，使创意能够更快地得到测试和审查。拟议的工作大致分为以下几个领域。1)建立了基于Thole偏振方案的全极化模型。这样的力场有望改善生物分子与二价离子、药物和环境相互作用的表示；2)将开发一个新的隐式溶剂模型，以包括固定和动态的溶剂和溶质极化率；3)将进一步发展加法和联合原子模型，以开发包含关键极化效应的混合模型，其计算成本与典型的定点电荷模型相当，并改进侧链参数，以改进对能量表面的表示；4)发展一般的琥珀力场(GAFF)模型将允许更准确地表示不同的类药物分子与由改进的加性和极化力场代表的生物分子的相互作用；5)模拟方法和相关参数将通过与实验的直接比较进行严格的审查和严格的评估。

DESCRIPTION (provided by applicant): Molecular simulations have played important roles in biochemical and biophysical sciences. Advances have been made that have allowed extensive simulations of increasingly complex systems. Furthering these advances, this group of investigators proposes to establish a consortium to develop parameters and simulation methodologies that are part of the foundation of molecular simulation platform. The proposed consortia brings together a group of young researchers, all former members of the Kollman lab at UCSF, to push the "Amber" force field efforts to the next level. These investigators have made significant contributions :o the development of both Amber simulation package and the force field parameters and have undertaken significant collaboration in the past which is evident by many joint publications among the authors. A key focus of this proposal is to not only develop general, reliable and widely applicable force fields for proteins, nucleic acids and drug-like molecules, but to validate the force fields via thorough testing and comparison to other available methods and force fields. At present, the choices to make in terms of the model (polarization, charge model, solvent representation) are still active research questions. This proposal is broad-reaching in that multiple approaches will be investigated, ranging from development of next generation general-purpose polarizable force field to models specifically designed to take advantage of continuum solvent. From the team assembled, considerable expertise in the simulation of proteins and nucleic acids is evident which will help guide the efforts forward. A key objective of the consortium is to further enhance the close collaboration that allows ideas to be tested and vetted much more quickly. The proposed work is broadly categorized in the following areas. 1) A fully polarizable model based on Thole's scheme of polarization will be developed. Such a force field is expected to improve the representation of biomolecules interacting with divalent ions, drugs and the environment; 2) A new implicit solvent model will be developed to incorporate both fixed and dynamic solvent and solute polarizability; 3) Further development of additive and united-atom models will be pursued to develop a hybrid model that incorporates the key polarization effect with a comparable computational cost to that of typical fixed point charge models and to refine the side chain parameters for an improved representation of the energetic surface; 4) Development of the general Amber force field (GAFF) model will allow more accurate representation of diverse sets of drug-like molecules interacting with biomolecules represented by improved additive and polarizable force fields; 5) The simulation methodology and the associated parameters will be vigorously scrutinized and critically assessed through direct comparisons with experiments.