Molecular Dynamics Simulations of Proteins and Peptides: Problems, Achievements, and Perspectives

Tavan, Paul; Carstens, Heiko; Mathias, Gerald

doi:10.1002/9783527619498.ch33

Cited by 17 publications

(20 citation statements)

References 53 publications

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“…These force fields model the electrostatic signatures of molecules or of molecular fragments by static partial charges localized at the atoms and, therefore, can account for the effects of electronic polarization only by the mean field approximation, which is highly questionable for inhomogeneous and non-isotropic biomolecular systems. 7 There are notable exceptions which combined a polarizable force field for the MM fragment with semiempirical quantum chemistry for the QM fragment. [8][9][10][11][12] Combinations of higher-level QM treatments (density functional a) Electronic mail: gerald.mathias@physik.uni-muenchen.de theory 13,14 (DFT) or ab initio quantum chemistry) with PMM force fields were either restricted to the energetics of static systems, [15][16][17][18][19][20][21][22][23] to small molecular clusters, [24][25][26][27][28][29] or describe the dynamics only in parts of the simulation system.…”

Section: Introductionmentioning

confidence: 99%

Coupling density functional theory to polarizable force fields for efficient and accurate Hamiltonian molecular dynamics simulations

Schwörer

Breitenfeld

Tröster

et al. 2013

The Journal of Chemical Physics

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Hybrid molecular dynamics (MD) simulations, in which the forces acting on the atoms are calculated by grid-based density functional theory (DFT) for a solute molecule and by a polarizable molecular mechanics (PMM) force field for a large solvent environment composed of several 10 3 -10 5 molecules, pose a challenge. A corresponding computational approach should guarantee energy conservation, exclude artificial distortions of the electron density at the interface between the DFT and PMM fragments, and should treat the long-range electrostatic interactions within the hybrid simulation system in a linearly scaling fashion. Here we describe a corresponding Hamiltonian DFT/(P)MM implementation, which accounts for inducible atomic dipoles of a PMM environment in a joint DFT/PMM self-consistency iteration. The long-range parts of the electrostatics are treated by hierarchically nested fast multipole expansions up to a maximum distance dictated by the minimum image convention of toroidal boundary conditions and, beyond that distance, by a reaction field approach such that the computation scales linearly with the number of PMM atoms. Short-range over-polarization artifacts are excluded by using Gaussian inducible dipoles throughout the system and Gaussian partial charges in the PMM region close to the DFT fragment. The Hamiltonian character, the stability, and efficiency of the implementation are investigated by hybrid DFT/PMM-MD simulations treating one molecule of the water dimer and of bulk water by DFT and the respective remainder by PMM. © 2013 AIP Publishing LLC. [http://dx

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Section: Introductionmentioning

confidence: 99%

Coupling density functional theory to polarizable force fields for efficient and accurate Hamiltonian molecular dynamics simulations

Schwörer

Breitenfeld

Tröster

et al. 2013

The Journal of Chemical Physics

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“…Processes of protein folding and aggregation sensitively depend on the thermodynamic conditions and on a subtle balance of the electrostatic interactions within the proteinsolvent system (Warshel and Russell, 1984) which, therefore, have to be adequately represented in MD simulations (Tavan et al, 2005). To generate a well-defined thermodynamic ensemble in MD, one has to enclose the protein and a small (3-to 8-nm) neighborhood of solvent molecules by periodic boundaries (Allen and Tildesley, 1987).…”

Section: Introductionmentioning

confidence: 99%

“…To generate a well-defined thermodynamic ensemble in MD, one has to enclose the protein and a small (3-to 8-nm) neighborhood of solvent molecules by periodic boundaries (Allen and Tildesley, 1987). For an adequate treatment of the electrostatic interactions one has to apply either Ewald (Frenkel and Smit, 2002) or movingboundary reaction-field techniques (Mathias et al, 2003;Mathias and Tavan, 2005).…”

Section: Introductionmentioning

confidence: 99%

Molecular Dynamics Simulations Indicate a Possible Role of Parallel β-Helices in Seeded Aggregation of Poly-Gln

Stork

Giese

Kretzschmar

et al. 2005

Biophysical Journal

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The molecular structures of amyloid fibers characterizing neurodegenerative diseases such as Huntington's or transmissible spongiform encephalopathies are unknown. Recently, x-ray diffraction patterns of poly-Gln fibers and electron microscopy images of two-dimensional crystals formed from building blocks of prion rods have suggested that the corresponding amyloid fibers are generated by the aggregation of parallel beta-helices. To explore this intriguing concept, we study the stability of small beta-helices in aqueous solution by molecular dynamics simulations. In particular, for the Huntington aggregation nucleus, which is thought to be formed of poly-Gln polymers, we show that three-coiled beta-helices are unstable at the suggested circular geometries and stable at a triangular shape with 18 residues per coil. Moreover, we demonstrate that individually unstable two-coiled triangular poly-Gln beta-helices become stabilized upon dimerization, suggesting that seeded aggregation of Huntington amyloids requires dimers of at least 36 Gln repeats (or monomers of approximately 54 Gln) for the formation of sufficiently stable aggregation nuclei. An analysis of our results and of sequences occurring in native beta-helices leads us to the proposal of a revised model for the PrP(Sc) aggregation nucleus.

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“…Simulation systems addressing the bulk liquid should comprise several thousand water molecules − and corresponding MD simulations should cover several nanoseconds , for well-sampled computations of properties such as the dielectric constant. Here, DFT and other methods of quantum chemistry are excluded for reasons of computational manageability , and one must resort to less accurate but computationally much more efficient and preferentially polarizable , molecular mechanics (PMM) models.…”

Section: Introductionmentioning

confidence: 99%

Polarizable Six-Point Water Models from Computational and Empirical Optimization

2014

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Tröster et al. (J. Phys. Chem B 2013, 117, 9486-9500) recently suggested a mixed computational and empirical approach to the optimization of polarizable molecular mechanics (PMM) water models. In the empirical part the parameters of Buckingham potentials are optimized by PMM molecular dynamics (MD) simulations. The computational part applies hybrid calculations, which combine the quantum mechanical description of a H2O molecule by density functional theory (DFT) with a PMM model of its liquid phase environment generated by MD. While the static dipole moments and polarizabilities of the PMM water models are fixed at the experimental gas phase values, the DFT/PMM calculations are employed to optimize the remaining electrostatic properties. These properties cover the width of a Gaussian inducible dipole positioned at the oxygen and the locations of massless negative charge points within the molecule (the positive charges are attached to the hydrogens). The authors considered the cases of one and two negative charges rendering the PMM four- and five-point models TL4P and TL5P. Here we extend their approach to three negative charges, thus suggesting the PMM six-point model TL6P. As compared to the predecessors and to other PMM models, which also exhibit partial charges at fixed positions, TL6P turned out to predict all studied properties of liquid water at p0 = 1 bar and T0 = 300 K with a remarkable accuracy. These properties cover, for instance, the diffusion constant, viscosity, isobaric heat capacity, isothermal compressibility, dielectric constant, density, and the isobaric thermal expansion coefficient. This success concurrently provides a microscopic physical explanation of corresponding shortcomings of previous models. It uniquely assigns the failures of previous models to substantial inaccuracies in the description of the higher electrostatic multipole moments of liquid phase water molecules. Resulting favorable properties concerning the transferability to other temperatures and conditions like the melting of ice are also discussed.

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Molecular Dynamics Simulations of Proteins and Peptides: Problems, Achievements, and Perspectives

Cited by 17 publications

References 53 publications

Coupling density functional theory to polarizable force fields for efficient and accurate Hamiltonian molecular dynamics simulations

Coupling density functional theory to polarizable force fields for efficient and accurate Hamiltonian molecular dynamics simulations

Molecular Dynamics Simulations Indicate a Possible Role of Parallel β-Helices in Seeded Aggregation of Poly-Gln

Polarizable Six-Point Water Models from Computational and Empirical Optimization

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