SI2-SSE: Enhanced Software Tools for Biomolecular Free Energy Calculations

基于原子模拟的自由能计算在基础化学和生物学研究中的核心作用现已确立。自由能是指导系统在平衡或接近平衡时的行为的中心量，确定分子构象，分子结合，化学反应等特征。不幸的是，准确和可靠的自由能很难计算，特别是对于许多以崎岖的自由能景观为特征的生物分子系统。 因此，需要特殊的技术来计算这样的自由能景观。 在先前开发了所谓的自适应偏置分子动力学方法之后，通过其他方法（由我们小组开发或调整）进行相空间采样，该项目将进一步开发该软件的功能，从而扩大可以解决的模拟问题的种类。该软件将作为开源软件和AMBER软件包的一部分向公众发布。在科学应用方面，本计划亦将研究具有内序无序区的蛋白质的构象和性质，以及DNA与一类特殊转录因子的结合。自由能是描述生物分子和化学体系平衡状态的最重要的量。然而，计算自由能是出了名的困难和计算昂贵。这个问题对于许多生物分子系统来说尤其紧迫，这些系统的特征在于难以用常规分子动力学模拟探索的复杂自由能景观。PI先前开发了具有多个步行者的自适应偏置分子动力学方法（ABMD）和双交换分子动力学（REMD）扩展。ABMD是一种伞式采样方法，具有时间依赖性的偏置电位，用于计算自由能景观和构象采样。该软件套件，沿着与导向分子动力学（SMD）扩展，已发布给公众作为AMBER软件包的一部分。该项目将通过开发处理基于四元数的集体变量的能力，即所谓的里程碑技术和自我导向的交互式多个步行者，将这套软件工具提升到一个新的水平。设想的应用涉及具有内含子无序区（IDR）的蛋白质和通过转录因子中的碱性螺旋环受阻（bHLH）结构域结合DNA的机制。

The central role of atomistic simulation-based free energy calculations for basic chemical and biological research is now firmly established. The free energy is the central quantity that guides the behavior of a system at, or near, equilibrium, determining such characteristics as molecular conformations, molecular binding, chemical reactions, etc. Unfortunately, accurate and reliable free energies are very difficult to calculate, particularly for many biomolecular systems characterized by rugged free energy landscapes. Hence, special techniques are required for calculating such free energy landscapes. Having previously developed the so-called Adaptively Biased Molecular Dynamics method, enhanced with other methods (either developed or adapted by our group) for phase space sampling, this project will further develop the capabilities of this software thereby enlarging the kinds of simulation problems that can be tackled. The software will be released to the public as open source software and as parts of the AMBER software package. In terms of scientific applications, this project also will investigate the conformation and properties of proteins with Intrinsically Disordered Regions, and the binding of DNA with a special class of transcription factors.The single most important quantity for describing biomolecular and chemical systems in equilibrium is the free energy. However, calculating free energies is notoriously difficult and computationally expensive. This problem is particularly pressing for many biomolecular systems, which are characterized by complicated free energy landscapes that are hard to explore with regular molecular dynamics simulations. The PIs previously developed the Adaptively Biased Molecular Dynamics method (ABMD) with Multiple Walkers, and Replica Exchange Molecular Dynamics (REMD) extensions. ABMD is an umbrella sampling method with a time-dependent biasing potential for calculating free energy landscapes and conformational sampling. The software suite, along with Steered Molecular Dynamics (SMD) extensions, has been released to the public as part of the AMBER software package. This project will take this set of software tools to the next level by developing the capability to handle quaternion-based collective variables, the so-called Milestoning technique, and self-directed, interacting multiple walkers. Envisioned applications relate to proteins with Intrinsically Disordered Regions (IDRs) and mechanisms of DNA binding by basic Helix-Loop-Helix (bHLH) domains in transcription factors.