Coarse-Grained Directed Simulation.

Area of Science:

• Computational chemistry
• Molecular dynamics
• Biophysics

Background:

• Studying protein complexes often requires isolating components, leading to loss of native fluctuations due to environmental changes and imposed restraints.
• Accurate simulation estimates for subsystems within their native context necessitate preserving both structure and dynamics.

Purpose of the Study:

• To develop a new computational approach for simulating isolated protein components while retaining native fluctuations.
• To enable accurate free-energy sampling and quantum mechanics/molecular mechanics (QM/MM) studies of protein subsystems.

Main Methods:

• Utilized relative entropy minimization to incorporate experimental information into molecular simulations.
• Applied linear biases on coarse-grained (CG) observables to maintain target conformations and preserve equilibrium fluctuations.
• Developed algorithmic improvements to accelerate on-the-fly relative entropy minimization.

Main Results:

• Demonstrated the algorithm's efficacy by simulating an actin monomer/trimer in solution, matching fluctuations of actin within a filament.
• Successfully preserved native fluctuations of a subsystem within its larger biomolecular complex context.
• Integrated the developed methods into the PLUMED open-source software library.

Conclusions:

• The new method effectively maintains protein conformation and native fluctuations in isolated subsystems.
• This approach enhances the accuracy of molecular simulations for protein complexes.
• The contribution to the PLUMED library facilitates broader application of these advanced simulation techniques.