CHARMM force field, molecular modelling

In an attempt to aid interpretation of the IR spectrum of MbCO we decided to model the full protein by use of a hybrid quantum mechanics/molecular mechanics approach (QM/MM), to evaluate changes in the CO stretching frequency for different protein conformations. The QM/MM method used [44] combines a first-principles description of the active center with a force-field treatment (using the CHARMM force field) of the rest of the protein. The QM-MM boundary is modeled by use of link atoms (four in the heme vinyl and propionate substituents and one on the His64 residue). Our QM region will include the CO ligand, the porphyrin, and the axial imidazole (Fig. 3.13). The vinyl and propionate porphyrin substituents were not included, because we had previously found they did not affect the properties of the Fe-ligand bonds (Section 3.3.1). It was, on the other hand, crucial to include the imidazole of the proximal His (directly bonded to the... 

Hypercube, Inc. at http //www.hyper.com offers molecular modeling packages under the HyperChem name. HyperChem s newest version, Hyper-Chem Release 7.5, is a full 32-bit application, developed for the Windows 95, 98, NT, ME, 2000, and XP operating systems. Density Functional Theory (DFT) has been added as a basic computational engine to complement Molecular Mechanics, Semiempirical Quantum Mechanics and ab initio Quantum Mechanics. The DFT engine includes four combination or hybrid functions, such as the popular B3-LYP or Becke-97 methods. The Bio+ force field in HyperChem represents a version of the Chemistry at HARvard using Molecular Mechanics (CHARMM) force field. Release 7.5 of HyperChem updates... 

For the construction of molecular structures, a 2D formula editor is provided in combination with 3D conversion. Standard potential energy minimization is performed using the modified parameter set of the CHARMm force field [68] the conformational models are built using Monte Carlo conformational analysis together with poling as described in the next section. 

We conclude this section by giving a topical example of the utility of conditional averages in considering molecularly complex systems (Ashbaugh et al, 2004). We considered the RPLC system discussed above (p. 5), but without methanol n-Ci8 alkyl chains, tethered to a planar support, with water as the mobile phase. The backside of the liquid water phase contacts a dilute water vapor truncated by a repulsive wall see Fig. 1.2, p. 7. Thus, it is appropriate to characterize the system as consistent with aqueous liquid-vapor coexistence at low pressure. A standard CHARMM force-field model (MacKerell Jr. et al, 1998) is used, as are standard molecular dynamics procedures - including periodic boimdary conditions - to acquire the data considered here. Our interest is in the interface between the stationary alkyl and the mobile liquid water phases at 300 K. 

Alanine dipeptide, see Fig. 10.30, is a useful model compound in that it contains the basic constituents of a peptide chain. Thus there are sp -sp backbone C-C bond, backbone N-C bonds and side-chain C-C bonds. The torsions about each of these bonds are denoted as F, O and % respectively. The compound in the solid state has been modelled by molecular mechanics using the CHARMM force field [76]. The best results required non-zero force constants for the T and O torsions. Fig. 10.31 compares the experimental spectrum with the calculated one. There is a uniform mismatch in frequencies of 35 cm", but the overall pattern is reproduced. The individual contributions of the methyl groups... 

It is useful to point out that two sensitivity coefficients associated with parameters of the same type may give different sensitivities. For example, it is common in current biomolecular force fields to use the same force field parameter for chemically similar groups (e.g., the atomic partial charges for all the amide nitrogens have the same value in commonly used force fields such as those in the GROMOS, CHARMM, and AMBER molecular modeling packages). 

The rhodopsin protein problem An all-atom rhodopsin protein was set in a solvated lipid bilayer described via the Chemistry at Harvard Molecular Mechanics (CHARMM) force field. Long-range coulomb interactions were described via the particle-particle mesh. SHAKE constraints were applied to the system for the definitions of the force field and constraints. Further, the model consisted of counter ions with a reduced amount of water the effect was to have a total system with 32,000 atoms that was simulated for 100 time steps. This simulation was performed at a constant pressure and temperature with an LJ force cutoff of 10.0 Angstroms. In this problem, the total number of neighbors per atom was 440 within this force cutoff More information about the benchmark problem can be found at http //lammps.sandia.gOv/bench.html rhodo... 

The model represents the typical glycosphingoKpid/cholesterol content of the outer (exofacial) leaflet of a lipid raft present on the plasma membrane of astrocytes, oligodendrocytes, and neurons (obtained by molecular dynamics simulations with the HyperChem software, using the CHARMM force field). Cholesterol is in yellow. 

FIGURE 14.14 Molecular modeling of a Ca -permeable pore formed by a-synudein. The channel is formed by six monomers of a-syn67-79, each interacting with cholesterol. Two supplemental cholesterol molecules were then added to complete the structure (final stoichiometry 8 cholesterol/6 a-synuclein peptides). (A) The peptides are in yellow and cholesterol in atom colors. (B) Cholesterol is in yellow and the peptides in atom colors. Two views of the pore are shown (lateral and upside), with a Ca ion (gray disk, same scale as the other atoms) positioned at the entry of the pore. The models were obtained by molecular dynamics simulations with the CHARMM force field of the HyperChem program. 

AMBER A Program for Simulation of Biological and Organic Molecules Biomembranes Modeling CHARMM The Energy Function and Its Parameterization Environment of a Membrane Protein Force Fields A General Discussion GROMOS Force Field Molecular Dynamics Techniques and Applications to Proteins OPLS Force Fields Permeation of Lipid Membranes Molecular Dynamics Simulations Time Correlation Functions. 

Patel S, Mackerell AD, Brooks CL (2004) CHARMM fluctuating charge force field for proteins II -Protein/solvent properties from molecular dynamics simulations using a nonadditive electrostatic model. J Comput Chem 25(12) 1504-1514... 

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