New Solvent Models, Sampling Methods and Maintenance of Amber Software

项目摘要 本建议书是对PA-14-156《扩大发展、强化和传播 生物医学计算、信息学和大数据科学技术。这个目标 该计划旨在支持以下方面的持续开发、维护、测试和评估： 现有的软件，符合我们的建议。 Amber是一个非常受欢迎的软件包，被学术和工业机构用于模拟 分子系统的结构、热力学和动力学性质。Amber的免费版本 已被超过10，000个独立用户下载。有3,500条引用了广泛采用的 琥珀ff 99 SB蛋白力场，由PI卡洛斯·西默林在斯托尼布鲁克开发。The Simmerling 该小组是负责领导琥珀软件维护的六个学术实验室之一， 发展努力。 使用Amber和其他软件包进行的计算分子动力学模拟 成为实验研究的重要同行，以了解 生物分子，以及发现抑制它们的药物。流行的虚拟筛选程序称为 DOCK直接与Amber接口，为这个广泛使用的药物程序提供改进 的发现其他广泛使用的程序也与琥珀接口。 我们在上一个资助期的生产力非常好，导致在PNAS上发表的文章（2）， JACS（3），JCTC（4）和其他高影响力期刊，其他期刊目前正在审查中。几个新 Amber的版本已经发布。 我们在这里提出了琥珀的新发展，解决了两个最紧迫的需求， 外地目标1，溶剂化：我们将采用改进的溶剂化模型：（a）SEA半- 显式水模型和（B）快速但相当精确的广义Born隐式水模型 模型目标2，抽样：我们将增加快速和有针对性的抽样方法： 通用工具哈密顿交换和热交换分子动力学，（B） 采样环的快速动态环闭合和约束环闭合方法 构象 根据我们过去20年的实践，我们将公开分享我们的成果、参数和 方法，并将它们纳入Amber生产代码，以便完全 文档化的源代码，沿着完整的文档、测试用例和教程。新版本 遵循年度发布时间表。

Project Summary This proposal responds to PA-14-156, Extended Development, Hardening and Dissemination of Technologies in Biomedical Computing, Informatics and Big Data Science. The goal of this program is to support the continued development, maintenance, testing and evaluation of existing software, matching our proposal. Amber is a very popular software package, used by academic and industry institutions, for simulating the structural, thermodynamic and kinetic properties of molecular systems. The free version of Amber has been downloaded by over 10,000 unique users. There are 3,500 citations to the widely adopted Amber ff99SB protein force field, developed at Stony Brook by PI Carlos Simmerling. The Simmerling group is one of the six academic labs responsible for leading the Amber software maintenance and development effort. Computational molecular dynamics simulations using Amber and other software packages have become essential counterparts to experimental research for understanding the mechanisms of biomolecules, and for discovering drugs to inhibit them. The popular virtual screening program called DOCK interfaces directly with Amber, providing improvements to this widely used program for drug discovery. Other widely used programs also interface with Amber. Productivity in our prior funding period was excellent, leading to articles published in PNAS (2), JACS (3), JCTC (4) and other high-impact journals, with others currently in review. Several new versions of Amber were released. We propose here new developments for Amber, addressing two of the most pressing needs of the field. Aim 1, Solvation: We will incorporate improved solvation models: (a) the SEA semi- explicit water model and (b) a fast but reasonably accurate Generalized Born implicit water model. Aim 2, Sampling: We will add fast and targeted sampling methods: (a) variants of the general tools Hamiltonian exchange and thermal Replica Exchange Molecular Dynamics, (b) the very fast Kinetic-Loop-Closure and Constrained-Loop-Closure methods for sampling loop conformations. Following our practice over the past 20 years, we will openly share our results, parameters and methods, and incorporate them into the Amber production code for distribution with fully documented source code, along with full documentation, test cases, and tutorials. New versions follow an annual release schedule.