Estimating kinetic rates from accelerated molecular dynamics simulations: alanine dipeptide in explicit solvent as a...

Area of Science:

• Computational Chemistry
• Molecular Biophysics
• Biomolecular Simulation

Background:

• Molecular dynamics (MD) simulation is crucial for studying molecular system conformations over time.
• Standard MD struggles to access the slow conformational transitions relevant to many biological systems.
• Accelerated molecular dynamics (aMD) is a proposed method to overcome standard MD's time scale limitations.

Purpose of the Study:

• To evaluate the enhanced conformational sampling of the phi/psi space in alanine dipeptide using aMD in explicit water.
• To develop a framework for accurately recovering kinetic rate constants for slow conformational transitions.
• To determine the helix to beta-strand transition rate constant using aMD.

Main Methods:

• Utilized accelerated molecular dynamics (aMD) simulations for alanine dipeptide in explicit water.
• Analyzed the sampling efficiency of the phi/psi conformational space.
• Developed a method to estimate kinetic rate constants by relating diffusion coefficients to energy landscape roughness.

Main Results:

• aMD significantly enhanced the sampling of the phi/psi conformational phase space compared to standard MD.
• Free energy density plots confirmed accurate sampling of all minima regions and recovery of canonical distribution.
• The kinetic rate constant for the helix to beta-strand transition was accurately estimated using aMD.

Conclusions:

• Accelerated molecular dynamics provides superior conformational sampling over standard MD for biomolecular systems.
• The developed framework enables accurate estimation of kinetic rate constants for slow transitions, even for low-barrier events.
• Standard MD is insufficient for accurately determining rate constants of slow transitions, highlighting the utility of aMD.