New Solvent Models, Sampling Methods and Maintenance of Amber Software

项目摘要 本提案响应PA-14-156，扩展开发、强化和传播 生物医学计算、信息学和大数据科学技术。这样做的目的是 该计划旨在支持继续开发、维护、测试和评估 现有软件，符合我们的建议。 琥珀是一个非常流行的软件包，学术和工业机构使用它来模拟 分子体系的结构、热力学和动力学性质。免费版的琥珀 已有超过10,000名独立用户下载。被广泛采用的3500次引用 琥珀ff99Sb蛋白质力场，由Pi Carlos Simmerling在Stony Brook开发。《西默林》 集团是负责领导琥珀软件维护和 发展努力。 使用Amber和其他软件包的计算分子动力学模拟 成为实验研究的重要对应者，以了解 生物分子，以及发现抑制它们的药物。广受欢迎的虚拟筛选程序名为 Dock直接与Amber对接，为这一广泛使用的药物程序提供改进 发现号。其他广泛使用的程序也与琥珀接口。 我们上一个资助期的生产率非常高，导致在PNAS上发表了文章(2)， JJS(3)、JCTC(4)和其他影响较大的期刊，其他期刊目前正在审查中。几个新的 琥珀的不同版本已经发布。 我们在这里为琥珀提出新的发展，解决两个最紧迫的需求 田野。目标1，溶剂化：我们将纳入改进的溶剂化模型：(A)海洋半 显式水模型和(B)快速但相当精确的广义Born隐式水 模特。目标2，抽样：我们将增加快速和有针对性的抽样方法：(A) 通用工具哈密顿交换和热复制交换分子动力学，(B) 采样环的快速动力学闭环法和约束闭环法 构象。 遵循我们过去20年的实践，我们将公开分享我们的成果、参数和 方法，并将它们合并到琥珀生产代码中，以便与完整的 有记录的源代码，以及完整的文档、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.