# The critical helping hand of water: theory shows the way to obtain elusive, granular information about kinetic asymmetry driven systems

## TL;DR

This paper introduces a new computational method to study chemical systems where one product is selectively made, revealing how water dramatically speeds up molecular motor rotation.

## Contribution

A novel two-step computational approach combining DFT and Gillespie algorithm simulations is introduced to study kinetic asymmetry.

## Key findings

- Water increases the rotation rate constant of the final step by more than ten orders of magnitude.
- The approach explains the efficient rotation of gel-embedded molecular motors and sets an upper limit for rotation barriers.
- The method provides insights into the role of hidden factors like water in kinetic asymmetry-driven systems.

## Abstract

Kinetic asymmetry is crucial in chemical systems where the selective synthesis of one product over another, or the acceleration of specific reaction(s) is necessary. However, obtaining precise information with current experimental methods about the behavior of such systems as a function of time, substrate concentration and other relevant factors, is not possible. Computational chemistry provides a powerful means to address this problem. The current study unveils a two-pronged computational approach: (i) full quantum chemical studies with density functional theory (DFT), followed by (ii) stochastic simulations with a validated Gillespie algorithm (GA) (using representative model systems where necessary), to study the behavior of a kinetic asymmetry driven unidirectional molecular motor (1-phenylpyrrole2,2′-dicarboxylic acid) (Nature, 2022, 604 (7904), 80–85). Our approach allows us to understand what is really taking place in the system, underlining the crucial role played by water molecules in facilitating the rotation of the motor. It is seen that water lubricates the motion by increasing the rotation rate constant of the final step by, remarkably, more than ten orders of magnitude! These insights further serve to explain the efficient rotation of the very recently reported gel-embedded molecular motor (Nature, 2025, 637 (8046), 594–600), providing an upper limit for the allowed rotation barrier in such systems, and thus also casts light into the functioning of bio-molecular motors. The current work therefore provides a template for carefully and properly studying a wide variety of important, kinetic asymmetry driven systems in the future.

Through computational studies, we show that powerful hidden factors, such as the water effect on the rotation of a molecular motor, can be captured. Our approach can be employed to understand a wide range of kinetic asymmetry driven systems.