• 2025-06-27
• in Physical-Chemistry, Metadynamics
• 43 min read

Practicing Metadynamics on the Müller-Brown Potential Energy Surface

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1. Introduction to Metadynamics

Based on my interest in the molecular dynamics(MD)¹, my advisor recommended that I learn the PLUMED² plugin to deepen my understanding of MD capabilities and become familiar with state-of-the-art enhanced sampling techniques.

After hearing this advice, I did some research and discovered the PLUMED Masterclasses³ which gather experts to explain cutting-edge methods and how to solve challenging problems. In this post, I will explain some parts of Masterclass 9. In some blog post in the future I will proved some challenges with the production of the state-of-art pipeline for the drug testing of the preclinical phase. That will only be our concern. In the multiple posts I will try to provide the path to getting the understanding of the highly accurate meta dynamics-based calculation⁴ of protein-protein and protein-ligand binding potencies.

As a motivation, I was inspired by recent research on glycine formation. In that work, glycine was hypothesized to form stepwise from smaller molecules and was investigated using exploratory CPMD⁵ and free energy simulations⁶. Ab Initio Study of Glycine Formation in the Condensed Phase: Carbon Monoxide, Formaldimine, and Water Are Enough provides the basis for much of this blog post. This study served as my entry point into the field.

Fig 1 Stepwise reactions observed in the glycine formation study (Francisco Carrascoza et al 2023). This diagram from the article shows a sequence of reactions (system S3V0) starting from carbon monoxide and formaldimine in water and ultimately forming glycine. (We will not delve into these specific reactions here; Figure 1 is meant to illustrate the kind of complex pathways metadynamics can discover.)

When I came across the lecture on reaction pathways⁷, I was able to put this idea into practice, but first I need to work through the simpler examples.