Multiscale Modeling Tools for Protein Structure and Dynamics Simulations

Recently we developed a suite of tools for a multiscale computational approach to protein structure prediction and modeling protein dynamics on biologically important time-scales. Our recent studies show, that reduced modeling emploing knowledge-based, statistical potentials derived from known structures, is applicable in simulations of protein denatured state, protein folding initiation and mechanism studies [1, 2, 3].

The multiscale simulations are based on the idea of hierarchical approach. Coarse-grained effective search of the conformational space by the CABS model [4] is followed by reliable transition into the all-atom resolution [5], subsequent fine-tuning and assessment of the final models [6]. The CABS model, being the central element of the procedure, has been extensively tested in numerous applications, including studies of protein long time dynamics and thermodynamics, protein structure prediction and protein-protein docking.

Thus, presented tools and methods enable multiscale studies, on the level of individual residues, of the processes far beyond of capabilities of the classical methods (Molecular Dynamics), in terms of time-scales, as well as protein size.

Coarse-grained modeling stage

Reduced modeling with statistical potentials enable studying long-time protein dynamics [1, 2]. The reduced representation of a protein and the statistical potentials in the CABS model are outlined below.

Resulted protein models can be subjected to protein reconstruction procedure.

Procedure for protein reconstruction from alpha carbon coordinates and subsequent models assessment suited for the high-resolution structure prediction.

The procedure compose of the three following steps:

• protein backbone reconstruction by the use of BBQ - an algorithm for protein backbone reconstruction that comprises very high computational efficiency with high accuracy [5].
• side chains reconstruction which should be performed as accurate as possible by one of the available methods adjusting side chain rotamers to the existing backbone e.g. SCWRL
• protein models assessment by the use of Molecular Mechanics with fixed alpha carbons to rank-order the all-atom models built on the scaffolds of the reduced models [6].

The procedure can be effectively used in a large-scale studies:

• after reduced modeling stage either as a final step in protein structure prediction protocol [6] or in multiscale studies of protein dynamics [1, 2]
• when structures from different sources (and of different quality) are being compared

[1] S. Kmiecik and A. Kolinski. Characterization of Protein Folding Pathways by Reduced-space Modeling. Proc. Natl. Acad. Sci. USA, 104(30):12330-5, 2007

Description of chymotrypsin inhibitor (CI2) and barnase folding mechanisms by the use of coarse-grained modeling and statistical potentials (CABS model).

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[2] S. Kmiecik and A. Kolinski. Folding pathway of the B1 domain of protein G explored by a multiscale modeling.Biophysical Journal, 94: 726-736, 2008

Detailed characterization of B1 domain of protein G folding mechanism

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[3] S. Kmiecik, M. Kurcinski, A. Rutkowska, D. Gront, A. Kolinski. Denatured proteins and early folding intermediates simulated in a reduced conformational space. Acta Biochim. Pol. 53:131-143, 2006

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[4] A. Kolinski. Protein modeling and structure prediction with a reduced representation. Acta Biochim. Pol. 51:349-371, 2004

Detailed description of the CABS model

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[5] D. Gront, S. Kmiecik, A. Kolinski. Backbone Building from Quadrilaterals. A fast and accurate algorithm for protein backbone reconstruction from alpha carbon coordinates. J. Comput. Chemistry 28(9):1593-1597, 2007

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[6] S. Kmiecik, D. Gront, A. Kolinski. Towards high-resolution protein structure prediction. Fast refinement of reduced models with all-atom force field. BMC Structural Biology 7:43, 2007

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