The efficiency of MD simulations for hydrogen-rich systems, such as proteins in aqueous environments, can be enhanced through two primary methodologies: constraining the degrees of freedom associated with hydrogen atoms or augmenting their effective masses. These approaches aim to mitigate the computational burden imposed by high-frequency vibrations involving hydrogen atoms. To expedite simulations, constraint algorithms such as SHAKE and SETTLE 32 are extensively employed. These methods impose holonomic constraints on bond lengths involving hydrogen atoms, effectively eliminating high-frequency vibrational modes while maintaining the overall stability and integrity of the simulated system. By suppressing these rapid oscillations, SHAKE and SETTLE facilitate the implementation of larger integration timesteps, typically up to 2 fs, which substantially reduces computational costs. This optimization is achieved without compromising the complex vibrational and rotational motions inherent in the remaining molecular system. The SHAKE algorithm, applicable to general molecular systems, iteratively solves for constraint forces to maintain specified bond lengths. Conversely, SETTLE, an analytical solution specifically designed for rigid water models, directly calculates the constrained positions and velocities of water molecules8. Both methods effectively increase the stability of MD simulations, allowing for more extensive sampling of configurational space within a given computational timeframe.