Authors
Sevim, A., Kocak, A.
Abstract
The molecular mechanics-generalized Born surface area method (MMGBSA) is one of the most commonly used end state approaches used for the calculation of the binding free energy towards computational drug design and screening studies. It is customary to break up the free energy into van der Waals, electrostatic, polar solvation (GB), and nonpolar solvation (SA) terms and then either correlate these terms with experiment or assign physical meaning to each term. Here, we demonstrate that this assumption of independent fitting coefficients for decomposed energy terms could be invalid. Through analytic derivation and large-scale molecular dynamics simulations, we show that (i) the protein and ligand Coulomb interaction energy and the GB solvation correction are almost perfectly collinear (R2[≥]0.99) reflecting their designed role as vacuum electrostatics plus solvent screening, and (ii) the van der Waals interaction and SA term likewise exhibit strong correlation, as both depend primarily on buried surface area. Interaction entropy and C2 entropy corrections are also found to be strongly dependent on underlying electrostatic fluctuations, further reinforcing redundancy. These findings hold both at the level of instantaneous trajectory fluctuations and when averaged across a diverse set of 139 protein-protein complexes and persist in both single-trajectory and three trajectory MMGBSA protocols. Our results caution against using decomposed MMGBSA terms as independent predictors in regression models and suggest instead combining correlated terms into effective polar, nonpolar, and entropic contributions. Our study provides a systematic diagnosis of collinearity in MMGBSA and highlights pathways toward more interpretable and statistically robust predictive modeling.
Preprint server:
bioRxiv
The authors list and abstract were imported from bioRxiv on 30 Jun 2026.
Advertisement
Stats
- Recommendations n/a n/a positive of 0 vote(s)
- Views 4
- Comments 0