QM/MM Methods for Biological Systems

Senn, Hans Martin; Thiel, Walter

doi:10.1007/128_2006_084

Cited by 427 publications

(464 citation statements)

References 685 publications

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“…To assign electronic structures to PC2 and PC3 and determine the respective Glu76 protonation states, invisible in our X-ray structures, we geometry-optimized several candidates using hybrid quantum mechanical (QM)/molecular mechanical (MM) potentials (30,31) and performed pure QM calculations on smaller derived models. Mössbauer and EPR parameter calculations were carried out with in-house codes (see the SI Appendix for details).…”

Section: Resultsmentioning

confidence: 99%

X-ray crystallographic and computational studies of the O ₂ -tolerant [NiFe]-hydrogenase 1 from Escherichia coli

Volbeda

Amara

Darnault

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

192

269

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The crystal structure of the membrane-bound O 2 -tolerant [NiFe]-hydrogenase 1 from Escherichia coli (EcHyd-1) has been solved in three different states: as-isolated, H 2 -reduced, and chemically oxidized. As very recently reported for similar enzymes from Ralstonia eutropha and Hydrogenovibrio marinus, two supernumerary Cys residues coordinate the proximal [FeS] cluster in EcHyd-1, which lacks one of the inorganic sulfide ligands. We find that the as-isolated, aerobically purified species contains a mixture of at least two conformations for one of the cluster iron ions and Glu76. In one of them, Glu76 and the iron occupy positions that are similar to those found in O 2 -sensitive [NiFe]-hydrogenases. In the other conformation, this iron binds, besides three sulfur ligands, the amide N from Cys20 and one Oϵ of Glu76. Our calculations show that oxidation of this unique iron generates the high-potential form of the proximal cluster. The structural rearrangement caused by oxidation is confirmed by our H 2 -reduced and oxidized EcHyd-1 structures. Thus, thanks to the peculiar coordination of the unique iron, the proximal cluster can contribute two successive electrons to secure complete reduction of O 2 to H 2 O at the active site. The two observed conformations of Glu76 are consistent with this residue playing the role of a base to deprotonate the amide moiety of Cys20 upon iron binding and transfer the resulting proton away, thus allowing the second oxidation to be electroneutral. The comparison of our structures also shows the existence of a dynamic chain of water molecules, resulting from O 2 reduction, located near the active site.[4Fe-3S] cluster | membrane-bound hydrogenase | Mössbauer spectroscopy | QM/MM | structure/function relationships

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Section: Resultsmentioning

confidence: 99%

X-ray crystallographic and computational studies of the O ₂ -tolerant [NiFe]-hydrogenase 1 from Escherichia coli

Volbeda

Amara

Darnault

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

192

269

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“…[3][4][5] The practical application of many of these methods has been reviewed recently. 2 The pseudobond method, originally developed in our laboratory, provides a straightforward way to smoothly interface the QM and MM subsystems without introducing additional degrees of freedom into the system. This method has been applied successfully in numerous simulations of biomolecular systems ͑see for example, 6-10͒.…”

Section: A Boundary Problem In Qm/mm Simulationsmentioning

confidence: 99%

“…As a result, macromolecular systems are often partitioned into a reactive QM subsystem and a classical MM subsystem that provide a reasonable environment in which reactions may take place. Combined QM/MM methods 1,2 thus enable the simulation of chemical reactions in large biological systems.…”

Section: Introductionmentioning

confidence: 99%

A pseudobond parametrization for improved electrostatics in quantum mechanical/molecular mechanical simulations of enzymes

Parks

Cohen

et al. 2008

The Journal of Chemical Physics

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The pseudobond method is used in quantum mechanical/molecular mechanical ͑QM/MM͒ simulations in which a covalent bond connects the quantum mechanical and classical subsystems. In this method, the molecular mechanical boundary atom is replaced by a special quantum mechanical atom with one free valence that forms a bond with the rest of the quantum mechanical subsystem. This boundary atom is modified through the use of a parametrized effective core potential and basis set. The pseudobond is designed to reproduce the properties of the covalent bond that it has replaced, while invoking as small a perturbation as possible on the system. Following the work of Zhang ͓J. Chem. Phys. 122, 024114 ͑2005͔͒, we have developed new pseudobond parameters for use in the simulation of enzymatic systems. Our parameters yield improved electrostatics and deprotonation energies, while at the same time maintaining accurate geometries. We provide parameters for C ps ͑sp 3 ͒ -C͑sp 3 ͒, C ps ͑sp 3 ͒ -C͑sp 2 , carbonyl͒, and C ps ͑sp 3 ͒ -N͑sp 3 ͒ pseudobonds, which allow the interface between the quantum mechanical and molecular mechanical subsystems to be constructed at either the C ␣ -C ␤ bond of a given amino acid residue or along the peptide backbone. In addition, we demonstrate the efficiency of our parametrization method by generating residue-specific pseudobond parameters for a single amino acid. Such an approach may enable higher accuracy than general purpose parameters for specific QM/MM applications.

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“…To cope with the multiple length-scale problem of complex protein systems, several multiscale-modeling methods have been proposed, which partition a complex system in different space regions with varying degree of chemical resolution defined in an ad hoc fashion prior to the simulation. They rely on the idea of coupling theoretical methods with different levels of coarsegraining, i.e., quantum, atomistic, mesoscopic, or continuumscale approaches, [23][24][25][26][27] within one simulation method. However, such techniques generally lack transferability, because they are specifically adapted to the nature of the physical problem under consideration and, thus, are not suitable for reproducing the multiscale relaxation dynamics of complex protein systems far from equilibrium.…”

Section: Introductionmentioning

confidence: 99%

A novel computer simulation method for simulating the multiscale transduction dynamics of signal proteins

Peter

Dick

Baeurle

2012

The Journal of Chemical Physics

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Signal proteins are able to adapt their response to a change in the environment, governing in this way a broad variety of important cellular processes in living systems. While conventional moleculardynamics (MD) techniques can be used to explore the early signaling pathway of these protein systems at atomistic resolution, the high computational costs limit their usefulness for the elucidation of the multiscale transduction dynamics of most signaling processes, occurring on experimental timescales. To cope with the problem, we present in this paper a novel multiscale-modeling method, based on a combination of the kinetic Monte-Carlo-and MD-technique, and demonstrate its suitability for investigating the signaling behavior of the photoswitch light-oxygen-voltage-2-Jα domain from Avena Sativa (AsLOV2-Jα) and an AsLOV2-Jα-regulated photoactivable Rac1-GTPase (PA-Rac1), recently employed to control the motility of cancer cells through light stimulus. More specifically, we show that their signaling pathways begin with a residual re-arrangement and subsequent H-bond formation of amino acids near to the flavin-mononucleotide chromophore, causing a coupling between β-strands and subsequent detachment of a peripheral α-helix from the AsLOV2-domain. In the case of the PA-Rac1 system we find that this latter process induces the release of the AsLOV2-inhibitor from the switchII-activation site of the GTPase, enabling signal activation through effector-protein binding. These applications demonstrate that our approach reliably reproduces the signaling pathways of complex signal proteins, ranging from nanoseconds up to seconds at affordable computational costs.

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QM/MM Methods for Biological Systems

Cited by 427 publications

References 685 publications

X-ray crystallographic and computational studies of the O ₂ -tolerant [NiFe]-hydrogenase 1 from Escherichia coli

X-ray crystallographic and computational studies of the O ₂ -tolerant [NiFe]-hydrogenase 1 from Escherichia coli

A pseudobond parametrization for improved electrostatics in quantum mechanical/molecular mechanical simulations of enzymes

A novel computer simulation method for simulating the multiscale transduction dynamics of signal proteins

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QM/MM Methods for Biological Systems

Cited by 427 publications

References 685 publications

X-ray crystallographic and computational studies of the O 2 -tolerant [NiFe]-hydrogenase 1 from Escherichia coli

X-ray crystallographic and computational studies of the O 2 -tolerant [NiFe]-hydrogenase 1 from Escherichia coli

A pseudobond parametrization for improved electrostatics in quantum mechanical/molecular mechanical simulations of enzymes

A novel computer simulation method for simulating the multiscale transduction dynamics of signal proteins

Contact Info

Product

Resources

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X-ray crystallographic and computational studies of the O ₂ -tolerant [NiFe]-hydrogenase 1 from Escherichia coli

X-ray crystallographic and computational studies of the O ₂ -tolerant [NiFe]-hydrogenase 1 from Escherichia coli