Kinetics of barrier crossing events from temperature accelerated sliced sampling simulations

Area of Science:

• Computational Chemistry and Molecular Dynamics

Background:

• Temperature-accelerated sliced sampling (TASS) is an enhanced sampling technique for exploring high-dimensional collective variable (CV) spaces.
• TASS utilizes umbrella restraining biases, metadynamics biases, and temperature acceleration to achieve exhaustive sampling.
• Determining kinetic rate constants from free energy data generated by TASS simulations presents a significant challenge.

Purpose of the Study:

• To develop and validate a novel protocol for computing rate constants of barrier crossing events using TASS.
• To extend the applicability of TASS beyond free energy landscape exploration to kinetic analysis.
• To address the challenge of recovering kinetics from free energy data obtained from distinct TASS simulation slices.

Main Methods:

• Development of a protocol integrating artificial neural network (ANN)-based free energy landscape representation.
• Utilizing infrequent metadynamics in conjunction with TASS simulations.
• Applying the protocol to compute rate constants for molecular systems.

Main Results:

• Successfully computed accurate rate constants for the conformational change of alanine dipeptide in vacuo.
• Obtained reliable rate constants for the unbinding of benzamidine from trypsin.
• Validated the protocol by calculating rate constants for the unbinding of aspirin from β-cyclodextrin.

Conclusions:

• The proposed protocol effectively recovers kinetic information from TASS-generated free energy data.
• This advancement broadens the utility of TASS for comprehensive molecular dynamics studies, including kinetics.
• The method demonstrates accuracy across diverse molecular systems and processes.