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WIREs Comput Mol Sci
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Molecular dynamics simulations of macromolecular crystals

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The structures of biological macromolecules would not be known to their present extent without X‐ray crystallography. Most simulations of globular proteins in solution begin by surrounding the crystal structure of the monomer in a bath of water molecules, but the standard simulation employing periodic boundary conditions is already close to a crystal lattice environment. With simple protocols, the same software and molecular models can perform simulations of the crystal lattice, including all asymmetric units and solvent to fill the box. Throughout the history of molecular dynamics, studies of crystal lattices have served to investigate the quality of the underlying force fields, correlate the simulated ensembles to experimental structure factors, and extrapolate the behavior in lattices to behavior in solution. Powerful new computers are enabling molecular simulations with greater realism and statistical convergence. Meanwhile, the advent of exciting new methods in crystallography, including femtosecond free‐electron lasers and image reconstruction for time‐resolved crystallography on slurries of small crystals, is expanding the range of structures accessible to X‐ray diffraction. We review past fusions of simulations and crystallography, then look ahead to the ways that simulations of crystal structures will enhance structural biology in the future. This article is categorized under: Molecular and Statistical Mechanics > Molecular Dynamics and Monte‐Carlo Methods Structure and Mechanism > Computational Biochemistry and Biophysics
A selected interface of the pectin lyase protein crystal from PDB structure 1QCX. In the left panel, the β‐barrel structure is evident in the repeating loops of the full color asymmetric unit (black = backbone or carbon, red = oxygen, blue = nitrogen, yellow = sulfur) as well as the orange‐colored neighboring unit. Near and far clipping was used to show this interface without occlusion by other nearby asymmetric units. This interface, typical of others in the lattice, does not involve tight protein: protein contacts. In the right panel, water molecules (both crystallographic and placed in an amount needed to fill the unit cell volume) within 4 Å of both the central asymmetric unit and at least one of its neighbors are shown as solid blue spheres. Water molecules within 8 Å of the central asymmetric unit and at least one of its neighbors are shown as faded blue spheres. As with the water, components of neighboring asymmetric units within 4 or 8 Å of the central unit are shown as solid or faded orange wiring, respectively. The “first solvent layer” enshrouds the central asymmetric unit, leaving little room for direct contacts with neighboring lattice proteins. This crystal, which is only 35% solvent (water and ions) by mass, shows how even a low amount of water is distributed to cover individual monomers in a protein crystal
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Centers of mass of the protein chain, projected onto the bc crystalographic plane; the origin represents the location in the starting structure (from PDB id 4LZT). Different colors represent each of the chains in a 12 unit cell simulation, and there are 100 equally spaced snapshots
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Isotropic B‐factors for Cα atoms in triclinic lysozyme. Black: refined against experimental data (PDB id 4LZT); red: refined against the average electron density from an MD simulation; purple: computed from the mean‐square structure fluctuations from the same simulation
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Backbone cartoons for hen egg white lysozyme. Orange represents the average simulated structure for 12 independent copies of the protein simulated as part of the same crystal, while black represents the X‐ray structure
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Structure and Mechanism > Computational Biochemistry and Biophysics
Molecular and Statistical Mechanics > Molecular Dynamics and Monte-Carlo Methods

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