Molecular Dynamics of the Intrinsically Disordered Protein COR15A─A Force Field Validation on Structure and Dynamics

Area of Science:

• Biophysics
• Computational Biology
• Protein Science

Background:

• Intrinsically disordered proteins (IDPs) lack stable structures, complicating experimental characterization.
• Molecular dynamics (MD) simulations offer potential for studying IDP dynamics but require specialized force fields.
• Existing IDP force fields' performance in capturing conformational changes remains largely unevaluated.

Purpose of the Study:

• To assess the accuracy of 20 molecular dynamics (MD) force fields for simulating the intrinsically disordered protein COR15A.
• To evaluate the ability of these models to capture subtle structural and dynamic differences, including those induced by mutations.
• To identify the most suitable MD model for future studies of IDP conformational ensembles.

Main Methods:

• Validation of 20 MD models using short (200 ns) simulations compared against small-angle X-ray scattering (SAXS) data.
• In-depth analysis of the six best-performing models using extended (1.2 μs) simulations.
• Comparison with nuclear magnetic resonance (NMR) data, including relaxation times and a single-point mutant.

Main Results:

• Only two force fields (DES-amber, ff99SBws) captured mutation-induced helicity changes, with ff99SBws overestimating helicity.
• DES-amber accurately reproduced COR15A's dynamics, as confirmed by NMR relaxation data at multiple magnetic field strengths.
• No single force field perfectly reproduced all experimental data, indicating ongoing challenges in IDP simulation.

Conclusions:

• DES-amber is the most effective MD model among those tested for simulating COR15A's structural and dynamic properties.
• Rigorous validation of force fields against experimental data is crucial for accurate IDP simulations.
• Further development of IDP-specific force fields is necessary to address remaining discrepancies and improve simulation accuracy.