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J Phys Chem B
2012 Jul 26;11629:8584-603. doi: 10.1021/jp212634z.
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Analysis and elimination of a bias in targeted molecular dynamics simulations of conformational transitions: application to calmodulin.
Ovchinnikov V
,
Karplus M
.
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The popular targeted molecular dynamics (TMD) method for generating transition paths in complex biomolecular systems is revisited. In a typical TMD transition path, the large-scale changes occur early and the small-scale changes tend to occur later. As a result, the order of events in the computed paths depends on the direction in which the simulations are performed. To identify the origin of this bias, and to propose a method in which the bias is absent, variants of TMD in the restraint formulation are introduced and applied to the complex open ↔ closed transition in the protein calmodulin. Due to the global best-fit rotation that is typically part of the TMD method, the simulated system is guided implicitly along the lowest-frequency normal modes, until the large spatial scales associated with these modes are near the target conformation. The remaining portion of the transition is described progressively by higher-frequency modes, which correspond to smaller-scale rearrangements. A straightforward modification of TMD that avoids the global best-fit rotation is the locally restrained TMD (LRTMD) method, in which the biasing potential is constructed from a number of TMD potentials, each acting on a small connected portion of the protein sequence. With a uniform distribution of these elements, transition paths that lack the length-scale bias are obtained. Trajectories generated by steered MD in dihedral angle space (DSMD), a method that avoids best-fit rotations altogether, also lack the length-scale bias. To examine the importance of the paths generated by TMD, LRTMD, and DSMD in the actual transition, we use the finite-temperature string method to compute the free energy profile associated with a transition tube around a path generated by each algorithm. The free energy barriers associated with the paths are comparable, suggesting that transitions can occur along each route with similar probabilities. This result indicates that a broad ensemble of paths needs to be calculated to obtain a full description of conformational changes in biomolecules. The breadth of the contributing ensemble suggests that energetic barriers for conformational transitions in proteins are offset by entropic contributions that arise from a large number of possible paths.
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22409258
???displayArticle.pmcLink???PMC3406239 ???displayArticle.link???J Phys Chem B ???displayArticle.grants???[+]
Banavali,
The N-terminal end of the catalytic domain of SRC kinase Hck is a conformational switch implicated in long-range allosteric regulation.
2005, Pubmed
Banavali,
The N-terminal end of the catalytic domain of SRC kinase Hck is a conformational switch implicated in long-range allosteric regulation.
2005,
Pubmed
Benkovic,
A perspective on enzyme catalysis.
2003,
Pubmed
Bennett,
Domain swapping: entangling alliances between proteins.
1994,
Pubmed
Bertini,
Experimentally exploring the conformational space sampled by domain reorientation in calmodulin.
2004,
Pubmed
Best,
Biochemistry. Unfolding the secrets of calmodulin.
2009,
Pubmed
Bolhuis,
Transition path sampling: throwing ropes over rough mountain passes, in the dark.
2002,
Pubmed
Branduardi,
From A to B in free energy space.
2007,
Pubmed
Brooks,
CHARMM: the biomolecular simulation program.
2009,
Pubmed
Cecchini,
Allosteric communication in myosin V: from small conformational changes to large directed movements.
2008,
Pubmed
Chen,
Slow conformational dynamics and unfolding of the calmodulin C-terminal domain.
2007,
Pubmed
Chipot,
Exploring the free-energy landscape of a short peptide using an average force.
2005,
Pubmed
Chou,
Solution structure of Ca(2+)-calmodulin reveals flexible hand-like properties of its domains.
2001,
Pubmed
,
Xenbase
Coutsias,
Using quaternions to calculate RMSD.
2004,
Pubmed
Cui,
Allostery and cooperativity revisited.
2008,
Pubmed
E,
Simplified and improved string method for computing the minimum energy paths in barrier-crossing events.
2007,
Pubmed
Evenäs,
Backbone dynamics and energetics of a calmodulin domain mutant exchanging between closed and open conformations.
1999,
Pubmed
Frederick,
Conformational entropy in molecular recognition by proteins.
2007,
Pubmed
Geeves,
Structural mechanism of muscle contraction.
1999,
Pubmed
Golosov,
The mechanism of the translocation step in DNA replication by DNA polymerase I: a computer simulation analysis.
2010,
Pubmed
Grabarek,
Structure of a trapped intermediate of calmodulin: calcium regulation of EF-hand proteins from a new perspective.
2005,
Pubmed
Grubmüller,
Ligand binding: molecular mechanics calculation of the streptavidin-biotin rupture force.
1996,
Pubmed
Haberthür,
FACTS: Fast analytical continuum treatment of solvation.
2008,
Pubmed
Hoeflich,
Calmodulin in action: diversity in target recognition and activation mechanisms.
2002,
Pubmed
Houdusse,
Myosin motors: missing structures and hidden springs.
2001,
Pubmed
Hu,
Bias annealing: a method for obtaining transition paths de novo.
2006,
Pubmed
Huang,
A Comparison of Three Perturbation Molecular Dynamics Methods for Modeling Conformational Transitions.
2009,
Pubmed
Humphrey,
VMD: visual molecular dynamics.
1996,
Pubmed
Isralewitz,
Steered molecular dynamics investigations of protein function.
2001,
Pubmed
Itoh,
Entropic mechanism of large fluctuation in allosteric transition.
2010,
Pubmed
Izrailev,
Molecular dynamics study of unbinding of the avidin-biotin complex.
1997,
Pubmed
Johnson,
Calmodulin, conformational states, and calcium signaling. A single-molecule perspective.
2006,
Pubmed
Johnson,
Conformational coupling in DNA polymerase fidelity.
1993,
Pubmed
Joyce,
Function and structure relationships in DNA polymerases.
1994,
Pubmed
Junker,
Evidence for a broad transition-state ensemble in calmodulin folding from single-molecule force spectroscopy.
2010,
Pubmed
Junker,
Ligand-dependent equilibrium fluctuations of single calmodulin molecules.
2009,
Pubmed
Karplus,
Biomolecular motors: the F1-ATPase paradigm.
2004,
Pubmed
Kuboniwa,
Solution structure of calcium-free calmodulin.
1995,
Pubmed
Laio,
Escaping free-energy minima.
2002,
Pubmed
Li,
Conformational transition pathway in the allosteric process of calcium-induced recoverin: molecular dynamics simulations.
2009,
Pubmed
Li,
Analysis of functional motions in Brownian molecular machines with an efficient block normal mode approach: myosin-II and Ca2+ -ATPase.
2004,
Pubmed
Ma,
A dynamic analysis of the rotation mechanism for conformational change in F(1)-ATPase.
2002,
Pubmed
Ma,
Ligand-induced conformational changes in ras p21: a normal mode and energy minimization analysis.
1997,
Pubmed
Ma,
A dynamic model for the allosteric mechanism of GroEL.
2000,
Pubmed
Mackerell,
Extending the treatment of backbone energetics in protein force fields: limitations of gas-phase quantum mechanics in reproducing protein conformational distributions in molecular dynamics simulations.
2004,
Pubmed
Madhusoodanan,
Investigation of pathways for the low-pH conformational transition in influenza hemagglutinin.
2003,
Pubmed
Ovchinnikov,
Free energy of conformational transition paths in biomolecules: the string method and its application to myosin VI.
2011,
Pubmed
Ovchinnikov,
Mechanical coupling in myosin V: a simulation study.
2010,
Pubmed
Paci,
Forced unfolding of fibronectin type 3 modules: an analysis by biased molecular dynamics simulations.
1999,
Pubmed
Paci,
Unfolding proteins by external forces and temperature: the importance of topology and energetics.
2000,
Pubmed
Phillips,
Scalable molecular dynamics with NAMD.
2005,
Pubmed
Radhakrishnan,
Orchestration of cooperative events in DNA synthesis and repair mechanism unraveled by transition path sampling of DNA polymerase beta's closing.
2004,
Pubmed
Ren,
Transition pathways in complex systems: Application of the finite-temperature string method to the alanine dipeptide.
2005,
Pubmed
Schlitter,
Targeted molecular dynamics: a new approach for searching pathways of conformational transitions.
1994,
Pubmed
Schumacher,
Crystal structures of apocalmodulin and an apocalmodulin/SK potassium channel gating domain complex.
2004,
Pubmed
Shen,
Scanning the human proteome for calmodulin-binding proteins.
2005,
Pubmed
Swindells,
Pre-formation of the semi-open conformation by the apo-calmodulin C-terminal domain and implications binding IQ-motifs.
1996,
Pubmed
Tama,
Conformational change of proteins arising from normal mode calculations.
2001,
Pubmed
Valeyev,
Elucidating the mechanisms of cooperative calcium-calmodulin interactions: a structural systems biology approach.
2008,
Pubmed
Vigil,
Functional dynamics of the hydrophobic cleft in the N-domain of calmodulin.
2001,
Pubmed
Wilson,
The 1.0 A crystal structure of Ca(2+)-bound calmodulin: an analysis of disorder and implications for functionally relevant plasticity.
2000,
Pubmed
Wyttenbach,
The effect of calcium ions and peptide ligands on the relative stabilities of the calmodulin dumbbell and compact structures.
2010,
Pubmed
Zhang,
Calcium-induced conformational transition revealed by the solution structure of apo calmodulin.
1995,
Pubmed
Zheng,
Random walk in orthogonal space to achieve efficient free-energy simulation of complex systems.
2008,
Pubmed
van der Vaart,
Minimum free energy pathways and free energy profiles for conformational transitions based on atomistic molecular dynamics simulations.
2007,
Pubmed
van der Vaart,
Simulation of conformational transitions by the restricted perturbation-targeted molecular dynamics method.
2005,
Pubmed
van der Vaart,
The unfolding action of GroEL on a protein substrate.
2004,
Pubmed
