Temperature Accelerated Molecular Dynamics with Soft-Ratcheting Criterion Orients Enhanced Sampling by Low-Resolution...

Area of Science:

• Biochemistry
• Computational Biology
• Structural Biology

Background:

• Proteins exist in multiple conformations, challenging computational exploration.
• Enhanced sampling methods often lack focus, while targeted pulling introduces bias.

Purpose of the Study:

• Introduce soft-ratcheting temperature-accelerated molecular dynamics (sr-TAMD) for efficient conformational sampling.
• Utilize low-resolution or qualitative information to guide molecular dynamics simulations.

Main Methods:

• sr-TAMD couples temperature-accelerated molecular dynamics (TAMD) with a soft-ratcheting algorithm.
• The algorithm filters collective variable (CV) values based on predefined criteria.
• Applied to explore the inactive state of adenyl cyclase (AC) from Bordetella pertussis.

Main Results:

• sr-TAMD enhanced sampling of AC's conformational space, focusing on globular structures.
• Successfully sampled a diverse set of inactive AC conformations.
• Results align with hydrodynamic measurements indicating a more globular inactive state.

Conclusions:

• sr-TAMD effectively enhances and filters CV space exploration in molecular dynamics.
• Provides an extensive description of the inactive AC state, consistent with experimental findings.
• Offers a novel approach for studying protein conformational dynamics using limited data.