A Mode Evolution Metric to Extract Converged Reaction Coordinates for Biomolecular Conformational Transitions

27 February 2024, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


The complex multidimensional energy landscape of biomolecules makes the extraction of suitable non-intuitive collective variables (CVs) which describe their conformational transitions challenging. At present dimensionality reduction approaches and machine learning schemes are employed to obtain reaction coordinates from datasets sampled either from techniques like molecular dynamics (MD) simulations or structural databanks for biomolecules. However, a poor understanding of sampling convergence and completeness of the dataset seriously limits assessment of the quality of the extracted CVs. Here, we build upon statistically rigorous ideas of local equilibration to develop a Mode evolution Metric (MeM) which can extract quantitatively converged CVs from non-equilibrated MD simulations using dimensionality reduction or machine learning approaches. Specifically, we apply MEM to extract converged principal components for transitions in model potential energy landscapes of varying complexities and in solvated alanine dipeptide. Finally, we demonstrate a possible application of MeM in designing efficient biased sampling schemes to construct accurate energy landscape slices which link transitions between two states. MeM can help speed up the search for new minima around a biomolecular conformational state and enable the accurate estimation of thermodynamics for states lying on the energy landscape and descriptions of associated transitions.


Collective variables
Monte Carlo Sampling
Principal Component Analysis
Mode convergence
Reaction Coordinates
Biomolecular Conformational Transitions
Molecular Dynamics Simulations
Non-equilibrium Sampling
Energy Landscapes

Supplementary materials

Supporting Information File
Supporting information on Methods, Figures, and Tables.


Comments are not moderated before they are posted, but they can be removed by the site moderators if they are found to be in contravention of our Commenting Policy [opens in a new tab] - please read this policy before you post. Comments should be used for scholarly discussion of the content in question. You can find more information about how to use the commenting feature here [opens in a new tab] .
This site is protected by reCAPTCHA and the Google Privacy Policy [opens in a new tab] and Terms of Service [opens in a new tab] apply.