[gmx-users] Energy minimization: problems with ramachanrad score

Mark Abraham mark.abraham at anu.edu.au
Thu Jun 17 03:04:31 CEST 2010

----- Original Message -----
From: Thomas Evangelidis <tevang3 at gmail.com>
Date: Thursday, June 17, 2010 10:48
Subject: [gmx-users] Energy minimization: problems with ramachanrad score
To: gmx-users at gromacs.org

> I 'm trying to relax my homology models from steric clashes, and while searching for the appropriate minimization scheme, I came across this old thread:
> http://lists.gromacs.org/pipermail/gmx-users/2007-April/027043.html
> The authors in the cited paper have created near-native structures as a test set with RMSD 1.06 ± 0.14  Å over the native ones. Then they ran energy minimization in vacuo with l-bfgs for 10000 steps or until convergence to machine precision and they found that ordinary MM potentials (AMBER99, OPLS-AA, GROMOS96, and ENCAD) showed no significant improvement on the structures. On the contrary the last 3 were found to move the conformation away from the native state by 11%, 40%, and 44% respectively. They also tested their own 3 hybrid Knowledge-Based / Molecular Mechanics (KB/MM) potentials and found that the best performing was moving the structures by 11% closer to the native fold.
> Essentially they claimed that energy minimization with the ordinary MM potentials is rubbish! I have one remark to make on this. Their decoy set comprised no-native protein conformers with RMSD ~1A. I'm wondering if the results will be similar for RMSDs ~3A as in my case where I'm building homology models with average sequence identity to templates 25-30%? 
> And with respect to the original question, if you overdo it with energy minimization the Ramachandran scores do deteriorate. However if you stop at an intermediate step you can get the same score, bond lengths and angles but with less steric clashes. Is this improvement plasmatic as the authors claim, namely you have moved away from the native fold although stereochemically the model look good?  

    Without having actually read their paper... there's could easily be a kind of apples-and-oranges comparison going on. The local optimum resulting from a single EM using MM forcefields optimized for non-vacuum conditions on near-native folds in vacuo are being compared with (say) crystal structures for the fitness of those minima as a model of (presumably) what's around under biological conditions. I'd guess that there's an appreciable number of cases where this is a three-way absurdity...


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