Advances in theoretical and computational methodology will be presented that are designed to simulate complex (biomolecular and other soft matter) systems across multiple length and time scales. This bottom-up approach provides a systematic connection between all-atom (AA) molecular dynamics, coarse-grained (CG) modeling, and mesoscopic phenomena. At the heart of these concepts are methods for deriving CG models from molecular structures and their underlying atomic-scale interactions. An important component of our work in the past few years has been the concept of the “ultra-coarse-grained” (UCG) model and its associated computational implementation. In the UCG approach, the CG sites or “beads” can have internal states, much like quantum mechanical states, so the UCG model involves a conceptual abstraction beyond simply Newtonian or Langevin dynamics for the CG beads. These internal states help to self-consistently quantify a more complicated set of possible interactions within and between the CG sites, while still maintaining a high degree of coarse-graining in the modeling. The presence of the CG site internal states also greatly expands the possible range of systems amenable to accurate CG modeling, including quite heterogeneous systems such as aggregation of hydrophobes in solution, liquid-vapor and liquid-solid interfaces, and complex self-assembly processes such as occur for large multi-protein complexes. The development of bottom-up CG models from the underlying atomistic interactions also addresses special challenges in terms of the treatment of solvation,  multi-body correlations, representability, transferability, and the missing entropy in CG models. Recent breakthroughs in addressing these issues – especially by employing developments in machine learning – will be the main focus of my talk. As time allows, one “pay-off” application from our multi-year effort will focus on processes in HIV-1 virus replication, and especially on the assembly of the HIV-1 virus capsid from over one thousand proteins – a phenomenon involving a billion atoms or more over long timescales that cannot even be approached through AA MD simulation.

Ongoing advances in the theory and application of coarse-graining

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