Element:Software:Enabling Millisecond-Scale Biomolecular Dynamics

Computer simulation methods based on Molecular Dynamics (MD) have been used for decades to understand chemical and biochemical phenomena at the molecular level. MD is a very powerful tool that has enabled scientists to understand the behavior of molecules crucial for life such as proteins and nucleic acids. MD has also been used to understand diseases and develop new drugs. However, MD is limited in both the size of the systems that can be studied and the amount of time that can be simulated. Many complex phenomena relevant to life involve systems too large to study with MD, or require following the system for much longer times. An alternative to traditional MD called discontinuous molecular dynamics (DMD) has been shown to be much more efficient to study biomolecular processes. To date, however, the use of DMD has been limited due to its inability to take advantage of modern parallel computers. This project will develop a next-generation parallel DMD software that will enable the study of complex molecular phenomena involving larger systems and longer time scales. Detailed knowledge of such processes will considerably advance the development of new materials and drugs, and human health. The project team combines the computational and experimental expertise to successfully develop and validate a robust parallel DMD software framework. The software and results will be actively shared both with the computational simulation community and with the scientific and engineering community at large, contributing to the capability, capacity, and cohesiveness of the national cyber-infrastructure ecosystem. Furthermore, the results of this project will be used in outreach efforts geared toward the education and inclusion of minorities traditionally underrepresented in higher STEM education.

This project aims to develop an open software framework that enables multi-millisecond dynamic simulations of peptides and peptide-mimetics by implementing a parallel discontinuous molecular dynamics (DMD) package. Unlike current molecular dynamics (MD), which features limited simulation timescales, discontinuous molecular dynamics (DMD) assumes ballistic motion of the particles between interaction events and enables the study of phenomena across much longer time scales. To demonstrate the approach, the project will (1) develop a parallel version of existing serial DMD codes to enable extending simulation times from hundreds of microseconds to several milliseconds; (2) extend and improve the available DMD peptide force field, adding parameters for non-natural peptides and peptoids; and (3) develop software for translating interaction potentials from traditional MD to DMD. The project team possesses the complementary expertise necessary for this project, including coarse-grained models and force fields for complex polymers and peptoids, MD simulation of protein self-assembly and peptide-protein binding processes, synthesis of protein-binding peptides and peptoids, and measurement of thermodynamic and kinetic binding parameters. The tools resulting from this research will allow the scientific and engineering community to model and study very long time-scale phenomena, such as biopolymer folding, aggregation and inhibition of aggregation, fibril formation, and protein-binding. This toolbox shows great promise to not only accelerate innovation in the computational design of biomaterials, but also to impact the molecular simulation community focusing on highly complex systems, up to cell-level dynamics. Notably, this project is ideal for the National Science Foundation's Cyber-infrastructure for Sustained Scientific Innovation (CSSI), as it (i) contributes to the capability, capacity, and cohesiveness of the national cyberinfrastructure ecosystem by providing user-friendly open-source computational tools, (ii) actively engages CI experts and testers of our toolbox, who would potentially be its ultimate users, (iii) advances our current capabilities in developing bioactive peptides and peptoids, (iv) establishes plans and metrics that encourage measurement of progress and certify the quality of shared tools and results, and (iv) devise strategies to combine wide-access with long-term community-driven development and progress.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.