New Generation of General AMBER Force Field for Biomedical Research

项目摘要 分子模拟在生化和生物物理研究中起着至关重要的作用。它的主要特点 应用是破译小分子配体和分子间的相互作用 生物分子，尤其是蛋白质受体，因此高效的激动剂或拮抗剂可以 被发现可以增强或消除目标功能。尽管花费了巨大的努力在 尽管发展迅速，但要准确预测蛋白质与配体的结合仍然是非常具有挑战性的。要克服 挑战是，我们需要(1)开发一个高质量的分子力学力场(MMFF)来 准确描述模拟系统的能量，以及(2)应用抽样策略 这可以有效地对与状态转换相耦合的“隐藏”事件进行采样。少校 该项目的目标是开发和测试第三代通用琥珀部队 GAFF场(GAFF3)显著提高琥珀小分子作用力的质量 菲尔德。GAFF3将在研究生物分子-配体相互作用方面进行批判性评估，使用一种新的 基于图形处理器加速的𝜆动力学正交空间调谐算法。先进的 采样技术将保证我们的大分子-配体结合自由能计算 不会因现有的抽样问题而复杂化，以便能够客观地评估GAFF3。这个 研究包括三个具体目标：(1)利用ABCG2，一种新的物理电荷，开发GAFF3 在大规模溶剂化自由能方面表现出优越性能的模型 计算。将对药物和类药物筛选进行大规模从头计算 (2)对GAFF3的性能进行批判性评估 用途径自由能和终点自由能研究生物分子与配体的相互作用 方法使用GPU计算。OST抽样方法将不断发展，并 为这项评估工作实施；以及(3)应用各种战略来处理“困难” 由我们或我们的用户识别的分子。这些战略将包括精细的原子分类和 引入新的功能形式。我们认为，这些努力将使GAFF3能够接近 加法模型可能具有的性能限制。对这些研究的成功追求 AIMS将帮助我们克服在蛋白质-配体和核酸精确建模方面的挑战 酸-配体结合。

Project Summary Molecular simulation plays an essential role in biochemical and biophysical research. Its major application is to decipher molecular interactions between small molecule ligands and biomolecules, especially protein receptors, so that highly potent agonists or antagonists can be discovered to enhance or eradicate target functions. Despite tremendous efforts spent on development, it is still very challenging to accurately predict protein-ligand binding. To overcome the challenge, we need (1) to develop a high-quality molecular mechanics force field (MMFF) to accurately describe the energetics of the simulation systems, and (2) to apply a sampling strategy which can effectively sample “hidden” events that are coupled with state transitions. The major goal of this project is to develop and test the 3rd generation of the general-purpose AMBER force field of GAFF (GAFF3) to significantly improve the quality of the AMBER small molecule force field. GAFF3 will be critically evaluated in studying biomolecule-ligand interactions using a novel GPU-accelerated 𝜆-dynamics based orthogonal space tempering (OST) algorithm. The advanced sampling technique will guarantee that our macromolecule-ligand binding free energy calculations are not complicated by existing sampling issues so that GAFF3 can be objectively evaluated. The study includes three specific goals: (1) to develop GAFF3 utilizing ABCG2, a new physical charge model which has demonstrated its superior performance in large scale solvation free energy calculations. Large-scale ab initio calculations will be performed for drugs and druglike screening compounds to derive force field parameters; (2) to critically evaluate the GAFF3 performance in studying biomolecule-ligand interactions using both pathway-based and endpoint free energy methods using GPU computing. The OST sampling method will be continuously developed and implemented for this evaluation effort; and (3) to apply a variety of strategies to handle “difficult” molecules identified by us or our users. The strategies will include fine atom typing and introduction of new functional forms. We believe that these efforts will allow GAFF3 to approach the performance limit an additive model could have. The successful pursuit of these research aims will facilitate us to surmount the challenges in accurately modeling protein-ligand and nucleic acid-ligand binding.