Improvement of the treatment of loop structures in the UNRES force field by inclusion of coupling between backbone- and side-chain-local conformational states

Paweł Krupa; Adam K Sieradzan; S Rackovsky; Maciej Baranowski; Stanisław Ołldziej; Harold A Scheraga; Adam Liwo; Cezary Czaplewski

doi:10.1021/ct4004977

Improvement of the treatment of loop structures in the UNRES force field by inclusion of coupling between backbone- and side-chain-local conformational states

J Chem Theory Comput. 2013 Oct 8;9(10):10.1021/ct4004977. doi: 10.1021/ct4004977.

Authors

Paweł Krupa^#^{1

2}, Adam K Sieradzan^#¹, S Rackovsky^#^{2

3}, Maciej Baranowski⁴, Stanisław Ołldziej⁴, Harold A Scheraga², Adam Liwo¹, Cezary Czaplewski¹

Affiliations

¹ Faculty of Chemistry, University of Gdańsk, Wita Stwosza 63, 80-952 Gdańsk, Poland.
² Baker Laboratory of Chemistry and Chemical Biology, Cornell University, Ithaca, N.Y., 14853-1301, U.S.A.
³ Dept. of Pharmacology and Systems Therapeutics, The Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, U.S.A.
⁴ Intercollegiate Faculty of Biotechnology, University of Gdańsk and Medical University of Gdańsk, Kładki 24, 80-922 Gdańsk, Poland.

^# Contributed equally.

Abstract

The UNited RESidue (UNRES) coarse-grained model of polypeptide chains, developed in our laboratory, enables us to carry out millisecond-scale molecular-dynamics simulations of large proteins effectively. It performs well in ab initio predictions of protein structure, as demonstrated in the last Community Wide Experiment on the Critical Assessment of Techniques for Protein Structure Prediction (CASP10). However, the resolution of the simulated structure is too coarse, especially in loop regions, which results from insufficient specificity of the model of local interactions. To improve the representation of local interactions, in this work we introduced new side-chain-backbone correlation potentials, derived from a statistical analysis of loop regions of 4585 proteins. To obtain sufficient statistics, we reduced the set of amino-acid-residue types to five groups, derived in our earlier work on structurally optimized reduced alphabets, based on a statistical analysis of the properties of amino-acid structures. The new correlation potentials are expressed as one-dimensional Fourier series in the virtual-bond-dihedral angles involving side-chain centroids. The weight of these new terms was determined by a trial-and-error method, in which Multiplexed Replica Exchange Molecular Dynamics (MREMD) simulations were run on selected test proteins. The best average root-mean-square deviations (RMSDs) of the calculated structures from the experimental structures below the folding-transition temperatures were obtained with the weight of the new side-chain-backbone correlation potentials equal to 0.57. The resulting conformational ensembles were analyzed in detail by using the Weighted Histogram Analysis Method (WHAM) and Ward's minimum-variance clustering. This analysis showed that the RMSDs from the experimental structures dropped by 0.5 Å on average, compared to simulations without the new terms, and the deviation of individual residues in the loop region of the computed structures from their counterparts in the experimental structures (after optimum superposition of the calculated and experimental structure) decreased by up to 8 Å. Consequently, the new terms improve the representation of local structure.

Keywords: local interactions; physicochemical properties; proteins; statistical potentials.

Grants and funding

R01 GM014312/GM/NIGMS NIH HHS/United States