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

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.