Making optimal use of empirical energy functions: force-field parameterization in crystal space

Proteins
Elmar KriegerGert Vriend

Abstract

Today's energy functions are not able yet to distinguish reliably between correct and almost correct protein models. Improving these near-native models is currently a major bottle-neck in homology modeling or experimental structure determination at low resolution. Increasingly accurate energy functions are required to complete the "last mile of the protein folding problem," for example during a molecular dynamics simulation. We present a new approach to reach this goal. For 50 high resolution X-ray structures, the complete unit cell was reconstructed, including disordered water molecules, counter ions, and hydrogen atoms. Simulations were then run at the pH at which the crystal was solved, while force-field parameters were iteratively adjusted so that the damage done to the structures was minimal. Starting with initial parameters from the AMBER force field, the optimization procedure converged at a new force field called YAMBER (Yet Another Model Building and Energy Refinement force field), which is shown to do significantly less damage to X-ray structures, often move homology models in the right direction, and occasionally make them look like experimental structures. Application of YAMBER during the CASP5 structure prediction ...Continue Reading

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Citations

Sep 1, 2009·European Biophysics Journal : EBJ·Hanka VenselaarGert Vriend
Aug 16, 2008·Applied Microbiology and Biotechnology·Birgit HeinzeUwe T Bornscheuer
Jul 23, 2011·Applied Microbiology and Biotechnology·Jessica RehdorfUwe T Bornscheuer
Jan 28, 2009·Journal of Molecular Modeling·Peter PalencarMichal Kuty
Jan 14, 2011·Journal of Molecular Modeling·Osvaldo A MartinCarlos E Tonn
Mar 2, 2011·Journal of Molecular Modeling·Peter Palenčár, Tomáš Bleha
Jul 3, 2013·Journal of Computer-aided Molecular Design·Jan JakubíkVladimír Doležal
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Sep 24, 2010·The Journal of Physical Chemistry. B·David S CeruttiDavid A Case
Feb 6, 2013·Proceedings of the National Academy of Sciences of the United States of America·Xun ShangYi Zheng
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