Multiscale enhanced sampling of intrinsically disordered protein conformations

Area of Science:

• Computational biology
• Biophysics
• Protein dynamics

Background:

• Multiscale enhanced sampling (MSES) couples coarse-grained (CG) models with atomistic force fields to improve protein conformation sampling.
• Simulating intrinsically disordered proteins (IDPs) presents challenges due to their conformational flexibility.

Purpose of the Study:

• To refine the MSES technique for enhanced sampling of atomistic protein conformations.
• To develop an optimal MSES protocol for simulating the conformational ensembles of IDPs.
• To evaluate the efficacy of the refined MSES-soft asymptote (SA) protocols.

Main Methods:

• Refined MSES protocols with advanced Hamiltonian/temperature replica exchange schemes.
• Incorporation of additional parameters in the MSES coupling restraint potential.
• Evaluation using two model peptides with varying residual helicities.

Main Results:

• MSES-SA protocols demonstrated more reversible helix-coil transitions.
• Improved convergence on various ensemble conformational properties was observed.
• The study suggests a need for more detailed CG models for local IDP transitions.

Conclusions:

• The refined MSES-SA protocols enhance the simulation of protein conformational ensembles, particularly for IDPs.
• Optimized coupling restraints improve the accuracy of multiscale simulations.
• Further development in CG models is recommended for detailed IDP local dynamics.