Combining atomic-level Molecular Dynamics with
coarse-grained Monte-Carlo dynamics
Andrzej Koliński
Laboratory of Theory of Biopolymers, Faculty of Chemistry, University of Warsaw
http://www.biocomp.chem.uw.edu.pl
Bioinformatics 2013 / BIT13, 26-29 June 2013, Toruń, Poland
All-atom MD with explicit water
• Atomic-Level Characterization of the Structural
Dynamics of Proteins, Science, 2010
• How Fast-Folding Proteins Fold, Science, 2011
1 milisecond simulations
ANTON - David E. Shaw group
Different all-atom force-fields (explicit water) are:
- able to fold a protein into its native tertiary structure
- inconsistent in the description of a folding pathway
Simulations of near-native dynamics seem to be
essentially force-field independent.
M. Rueda, C. Ferrer-Costa, T. Meyer, A. Perez, J. Camps, A. Hospital, J. L. Gelpi,
M. Orozco, A consensus view of protein dynamics Proc. Natl. Acad. Sci. U.S.A.
104:796−801, 2007
Coarse-grained models
Coarse-grained models of moderate resolution
(~102 faster than all-atom MD)
Lattice
Kolinski et al.
Continuous
Baker et al.
Liwo et al.
CABS model
Force field
Short range conformational
propensities
Context-dependent pairwise
interactions of side groups
A model of main chain hydrogen bonds
Interaction parameters are modulated by
the predicted secondary structure and
account for complex multibody interactions
and the averaged effect of solvent
Sampling – Monte Carlo dynamics
A. Kolinski, Protein modeling and structure prediction with a reduced representation
Acta Biochimica Polonica 51:349-371, 2004
Reconstruction & optimization procedure
protein backbone
reconstruction
side chain
reconstruction
all-atom
minimization step
Protein dynamics
All-atom MD (A – Amber, C – Charmm, G – Gromos
and O – OPLS/AA force-fields) is consistent with CABS
stochastic dynamics (after a proper renormalizations)
at short time-scales (10 ns)
M. Jamroz, M. Orozco, A. Kolinski, S. Kmiecik, A Consistent View of Protein
Fluctuations from All-atom Molecular Dynamics and Coarse-Grained Dynamics
with Knowledge-based Force-field, J. Chem. Theory Comput. 9:19–125, 2013
J. Wabik, S. Kmiecik, D. Gront, M. Kouza, A. Kolinski, Combining CoarseGrained Protein Models with Replica-Exchange All-Atom Molecular Dynamics,
International Journal of Molecular Sciences 14:9893-9905, 2013.
CABS models
reconstructed
all-atom models
(AMBER)
Kmiecik, D. Gront, M. Kouza, A. Kolinski, From Coarse-Grained to Atomic-Level
Characterization of Protein Dynamics: Transition State for the Folding of B
Domain of Protein A, J. Phys. Chem. B 116:7026-7032, 2012
Dynamics: CABS and all-atoms MD
Example of residue fluctuation profiles
Benchmarks summary
Test set (10 ns
trajectories)
Compared data
Avg. Spearman’s corr.
coeff. between residue
fluctuation profiles
22 proteins
MD vs. CABS
(each one by 4 different
force fields)
0.70
393 non-redundant
proteins
(Amber force field)
0.70
MD vs. CABS
140 non-redundant and NMR vs. CABS
NMR solved proteins
NMR vs. MD
(Amber force field)
MD vs. CABS
(J Chem Theory Comput, 2013)
(Nucl Acid Res, 2013)
0.72 (yet unpublished )
0.65
0.69
http://biocomp.chem.uw.edu.pl/CABSflex
CABS-flex
PDB: 1BSN,
F1-ATPase subunit,
138 AA
CABS-flex
PDB: 1BSN,
F1-ATPase subunit,
138 AA
CABS-flex
PDB: 1BHE, polygalacturonase, 376 AA
CABS-fold: server for protein structure prediction
http://biocomp.chem.uw.edu.pl/CABSfold
CABS in structure prediction
M. Blaszczyk, M. Jamroz, S. Kmiecik, A. Kolinski, CABS-fold: server for the novo
and consensus-based prediction of protein structure, Nucleic Acids Research, 2013
Structure prediction (de-novo)
The predicted models (colored in
rainbow) are superimposed on native
structures (colored in magenta)
Modeling accuracy could be highly improved when combined with
compartive modeling.
A. Kolinski, J. M. Bujnicki, Generalized protein structure prediction based on
combination of fold-recognition with de novo folding and evaluation of models,
Proteins 61(S7):84-90, 2005
Structure
prediction
(homology modeling)
CASP9 examples
9th Community Wide
Experiment on the
Critical Assessment of
Techniques for Protein
Structure Prediction
CABS – docking and interactions
Simulations of induced folding (binding) of intrisingly disordered protein pKIG
with KIX domain
CABS – docking and interactions
Simulations of induced folding (binding) of intrisingly disordered protein
pKIG with KIX domain
Summary:
CABS could be easily combined with all-atom Molecular Dynamics and
used in studies of protein dynamics, interactions and structure prediction
LTB servers based on CABS tools:
URL: http://biocomp.chem.uw.edu.pl/CABSfold
URL: http://biocomp.chem.uw.edu.pl/CABSflex
M. Jamroz, A. Kolinski & S. Kmiecik, CABS-flex: server for fast simulation
of protein structure fluctuations, Nucleic Acids Research, 1-5, 2013
M. Blaszczyk, M. Jamroz, S. Kmiecik, A. Kolinski, CABS-fold: server
for the novo and consensus-based prediction of protein structure, Nucleic
Acids Research 1-6, 2013
Thank you!
Co-authors: Drs. Sebastian Kmiecik, Michał Jamróz,
Dominik Gront, Maciej Błaszczyk, Mateusz Kurciński, Jacek Wabik
and others ….