Molecular Latent Space Simulators for Distributed and Multimolecular Trajectories.

Area of Science:

• Computational Chemistry
• Molecular Dynamics
• Biophysics

Background:

• All-atom molecular dynamics (MD) simulations are limited by short time steps for capturing rare molecular events.
• Markov state modeling (MSM) extends timescales but requires configurational coarse-graining, losing resolution and increasing complexity for multimolecular systems.
• Latent space simulators (LSS) offer an alternative dynamical coarse-graining approach.

Purpose of the Study:

• To extend the Latent space simulator (LSS) formalism to handle short, discontinuous trajectories from distributed computing.
• To adapt LSS for multimolecular systems without exponential computational cost scaling.
• To generate ultralong, continuous molecular trajectories for improved sampling and analysis.

Main Methods:

• Developed a distributed LSS model using thousands of short simulations for a proteolysis-targeting chimera (PROTAC) complex.
• Created a multimolecular LSS architecture for simulating DNA oligomer dynamics (duplex hybridization and hairpin folding).
• Employed a three-step learning process: identifying slow dynamics, propagating in the slow subspace, and reconstructing trajectories.

Main Results:

• Generated ultralong continuous trajectories for a PROTAC complex, identifying metastable states and collective variables.
• Produced physically realistic ultralong trajectories for DNA oligomers, capturing hybridization and folding.
• Achieved enhanced precision in folding populations and timescales across varying temperatures and ion concentrations for DNA systems.

Conclusions:

• The enhanced LSS formalism efficiently generates long, continuous molecular trajectories from discontinuous data.
• This approach significantly reduces computational cost compared to traditional MD, improving sampling of rare events.
• The LSS extension is applicable to complex biological systems, aiding in therapeutic design (PROTACs) and understanding molecular mechanisms (DNA folding).