CHARMM Additive Force Field Research Articles

Charmm2gmx: An Automated Method to Port the CHARMM Additive Force Field to GROMACS.

CHARMM is one of the most widely used biomolecular force fields. Although developed in close connection with a dedicated molecular simulation engine of the same name, it is also usable with other codes. GROMACS is a well-established, highly optimized, and multipurpose software for molecular dynamics, versatile enough to accommodate many different force field potential functions and the associated algorithms. Due to conceptional differences related to software design and the large amount of numeric data inherent to residue topologies and parameter sets, conversion from one software format to another is not straightforward. Here, we present an automated and validated means to port the CHARMM force field to a format read by the GROMACS engine, harmonizing the different capabilities of the two codes in a self-documenting and reproducible way with a bare minimum of user interaction required. Being based entirely on the upstream data files, the presented approach does not involve any hard-coded data, in contrast with previous attempts to solve the same problem. The heuristic approach used for perceiving the local internal geometry is directly applicable for analogous transformations of other force fields.

Extension of the CHARMM Classical Drude Polarizable Force Field to N- and O-Linked Glycopeptides and Glycoproteins.

Molecular dynamic simulations are an effective tool to study complex molecular systems and are contingent upon the availability of an accurate and reliable molecular mechanics force field. The Drude polarizable force field, which allows for the explicit treatment of electronic polarization in a computationally efficient fashion, has been shown to reproduce experimental properties that were difficult or impossible to reproduce with the CHARMM additive force field, including peptide folding cooperativity, RNA hairpin structures, and DNA base flipping. Glycoproteins are essential components of glycoconjugate vaccines, antibodies, and many pharmaceutically important molecules, and an accurate polarizable force field that includes compatibility between the protein and carbohydrate aspect of the force field is essential to study these types of systems. In this work, we present an extension of the Drude polarizable force field to glycoproteins, including both N- and O-linked species. Parameter optimization focused on the dihedral terms using a reweighting protocol targeting NMR solution J-coupling data for model glycopeptides. Validation of the model include eight model glycopeptides and four glycoproteins with multiple N- and O-linked glycosylations. The new glycoprotein carbohydrate force field can be used in conjunction with the remainder of Drude polarizable force field through a variety of MD simulation programs including GROMACS, OPENMM, NAMD, and CHARMM and may be accessed through the Drude Prepper module in the CHARMM-GUI.

Isothermal Titration Calorimetry of Be2+ and Ca2+ with Phosphatidylserine Models Guides All-Atom Force Field Development for Lipid-Ion Interactions

Beryllium has multiple industrial applications, but its unsafe manufacturing is associated with developing chronic inflammation in lungs known as berylliosis. Although high incidence of berylliosis was linked to a specific MHC allele that causes immune hypersensitivity to Be2+, recent findings also indicate that Be2+ competes with Ca2+ for binding sites in phosphatidylserine (PS) and thus inhibits the recognition and phagocytosis of apoptotic cells, potentially causing necrotic inflammation. This study aims to develop additive force field parameters that would describe Be2+ competition for divalent ion binding sites on anionic lipids critical for many signaling processes. We started with Lennard-Jones parameters for Be2+ for the CHARMM additive force field based on interactions with water, including free energy of hydration and ion-monohydrate interaction energy and separation distance. The results from isothermal titration calorimetry (ITC) for the binding affinities of Be2+ and Ca2+ to dimethylphosphate and acetate revealed that Be2+ has a stronger affinity than Ca2+ for binding with both component molecules. The existing CHARMM parameters for Ca2+ showed significant overbinding to acetate, while the parameters recently developed for Be2+ resulted in overbinding to both component molecules. To adjust these affinities to fit the experimental free energies of binding, configuration probabilities and free energies of association from molecular dynamics simulations were used to develop Lennard-Jones interaction parameters between the ions and component molecules. Using the revised interaction parameters, binding energies of Be2+ and Ca2+ with pure DOPS (1,2-dioleoyl-sn-glycero-3-phospho-L-serine) monolayers were calculated using free energy perturbation and compared with binding affinities determined from Langmuir monolayer experiments, ITC measurements on soluble short-chain PS and DOPS liposomes.

Improved CHARMM Additive Force Field Parameters to Accurately Model Tyrosine-Choline Cation-π Interactions

Cation-π interactions between methylated ammonium groups and tyrosine amino acids have been shown to be important for epigenetic recognition motifs, choline-binding proteins, and for protein-lipid interactions. Accurately modeling cation-π interactions in biomolecular simulations remains a challenge due to the lack of explicit polarization or charge transfer effects. In this work, we investigate the nature of tyrosine-choline cation-π interactions by performing high-level Quantum Mechanical (QM) calculations and building Potential Energy Surfaces (PES). We benchmark QM levels of theory and find that SAPT2+/aug-cc-pVDZ level of theory performs well compared to large basis set CCSD(T). Further, we compared QM PES (using SAPT2+/aug-cc-pVDZ) to both additive CHARMM36 and Drude polarizable force field. With CHARMM36, the equilibrium distances are well captured while the interaction energies are underestimated for various approach angles of TMA with respect to phenol. While using the Drude polarizable force field, the interaction energies deviate less compared to target QM data. However, the obtained equilibrium geometries are slightly underestimated. The best agreement between force field and QM PES is obtained by modifying the Lennard-Jones potentials for selected atom pairs involved in phenol-TMA cation-π interactions. We performed MD simulations of a bilayer-bound bacterial phospholipase and calculate the occupancies of tyrosine-choline cation-π interactions. The cation-π occupancies obtained with the modified set correlate better with experimental data than those obtained with the CHARMM force field.

Polarizable empirical force field for acyclic polyalcohols based on the classical Drude oscillator.

A polarizable empirical force field for acyclic polyalcohols based on the classical Drude oscillator is presented. The model is optimized with an emphasis on the transferability of the developed parameters among molecules of different sizes in this series and on the condensed-phase properties validated against experimental data. The importance of the explicit treatment of electronic polarizability in empirical force fields is demonstrated in the cases of this series of molecules with vicinal hydroxyl groups that can form cooperative intra- and intermolecular hydrogen bonds. Compared to the CHARMM additive force field, improved treatment of the electrostatic interactions avoids overestimation of the gas-phase dipole moments resulting in significant improvement in the treatment of the conformational energies and leads to the correct balance of intra- and intermolecular hydrogen bonding of glycerol as evidenced by calculated heat of vaporization being in excellent agreement with experiment. Computed condensed phase data, including crystal lattice parameters and volumes and densities of aqueous solutions are in better agreement with experimental data as compared to the corresponding additive model. Such improvements are anticipated to significantly improve the treatment of polymers in general, including biological macromolecules.

Sophisticated Modeling Uncovers Atomic DNA Structure in Bacteriophage Φ29 Cavity

Sophisticated Modeling Uncovers Atomic DNA Structure in Bacteriophage Φ29 Cavity

Force Field for Monovalent, Divalent, and Trivalent Cations Developed under the Solvent Boundary Potential

Presented are parameters for mono-, di-, and trivalent cations compatible with the CHARMM additive force field and the TIP3P water model. Thermodynamic perturbation molecular dynamics simulations were performed for the cations located at the center of a TIP3P water sphere under a solvent boundary potential. A series of perturbations generated free energies of hydration indexed by the two Lennard-Jones parameters, ε and R(min). Interpolating the experimental free energies of hydration showed that multiple combinations of ε and R(min) values reproduced the free energies of hydration for each ion. To overcome this nonunique parameter problem, the hydration shell model in combination with an empirical scaling parameter was applied to assign values for each ion. R(min) values were then identified via interpolation of the calculated free energies of hydration. The presented parameters are anticipated to be of utility for simulations of ions, including ions complexed to proteins.

Extension of the CHARMM general force field to sulfonyl‐containing compounds and its utility in biomolecular simulations

Presented is an extension of the CHARMM General Force Field (CGenFF) to enable the modeling of sulfonyl-containing compounds. Model compounds containing chemical moieties such as sulfone, sulfonamide, sulfonate, and sulfamate were used as the basis for the parameter optimization. Targeting high-level quantum mechanical and experimental crystal data, the new parameters were optimized in a hierarchical fashion designed to maintain compatibility with the remainder of the CHARMM additive force field. The optimized parameters satisfactorily reproduced equilibrium geometries, vibrational frequencies, interactions with water, gas phase dipole moments, and dihedral potential energy scans. Validation involved both crystalline and liquid phase calculations showing the newly developed parameters to satisfactorily reproduce experimental unit cell geometries, crystal intramolecular geometries, and pure solvent densities. The force field was subsequently applied to study conformational preference of a sulfonamide based peptide system. Good agreement with experimental IR/NMR data further validated the newly developed CGenFF parameters as a tool to investigate the dynamic behavior of sulfonyl groups in a biological environment. CGenFF now covers sulfonyl group containing moieties allowing for modeling and simulation of sulfonyl-containing compounds in the context of biomolecular systems including compounds of medicinal interest.

Optimization of the CHARMM additive force field for DNA: Improved treatment of the BI/BII conformational equilibrium.

The B-form of DNA can populate two different backbone conformations: BI and BII, defined by the difference between the torsion angles ε and ζ (BI = ε-ζ < 0 and BII = ε-ζ > 0). BI is the most populated state, but the population of the BII state, which is sequence dependent, is significant and accumulating evidence shows that BII affects the overall structure of DNA, and thus influences protein-DNA recognition. This work presents a reparametrization of the CHARMM27 additive nucleic acid force field to increase the sampling of the BII form in MD simulations of DNA. In addition, minor modifications of sugar puckering were introduced to facilitate sampling of the A form of DNA under the appropriate environmental conditions. Parameter optimization was guided by quantum mechanical data on model compounds, followed by calculations on several DNA duplexes in the condensed phase. The selected optimized parameters were then validated against a number of DNA duplexes, with the most extensive tests performed on the EcoRI dodecamer, including comparative calculations using the Amber Parm99bsc0 force field. The new CHARMM model better reproduces experimentally observed sampling of the BII conformation, including sampling as a function of sequence. In addition, the model reproduces the A form of the 1ZF1 duplex in 75 % ethanol, and yields a stable Z-DNA conformation of duplex (GTACGTAC) in its crystal environment. The resulting model, in combination with a recent reoptimization of the CHARMM27 force field for RNA, will be referred to as CHARMM36.

CHARMM additive all-atom force field for carbohydrate derivatives and its utility in polysaccharide and carbohydrate-protein modeling.

Monosaccharide derivatives such as xylose, fucose, N-acetylglucosamine (GlcNAc), N-acetylgalactosamine (GlaNAc), glucuronic acid, iduronic acid, and N-acetylneuraminic acid (Neu5Ac) are important components of eukaryotic glycans. The present work details development of force-field parameters for these monosaccharides and their covalent connections to proteins via O-linkages to serine or threonine sidechains and via N-linkages to asparagine sidechains. The force field development protocol was designed to explicitly yield parameters that are compatible with the existing CHARMM additive force field for proteins, nucleic acids, lipids, carbohydrates, and small molecules. Therefore, when combined with previously developed parameters for pyranose and furanose monosaccharides, for glycosidic linkages between monosaccharides, and for proteins, the present set of parameters enables the molecular simulation of a wide variety of biologically-important molecules such as complex carbohydrates and glycoproteins. Parametrization included fitting to quantum mechanical (QM) geometries and conformational energies of model compounds, as well as to QM pair interaction energies and distances of model compounds with water. Parameters were validated in the context of crystals of relevant monosaccharides, as well NMR and/or x-ray crystallographic data on larger systems including oligomeric hyaluronan, sialyl Lewis X, O- and N-linked glycopeptides, and a lectin:sucrose complex. As the validated parameters are an extension of the CHARMM all-atom additive biomolecular force field, they further broaden the types of heterogeneous systems accessible with a consistently-developed force-field model.

Calculation of the Vibrational Stark Effect Using a First-Principles Quantum Mechanical/Molecular Mechanical Approach

The proper description of the electric environment of condensed phases is a critical challenge for force field methods. To test and validate the ability of the CHARMM additive force field to describe the electric environment in aqueous solution combined QM/MM calculations have been used to calculate the vibrational Stark effect (VSE). We utilized a first principles methodology using correlated electronic structure techniques to compute the Stark shift between the gas phase and solvent environments and between two different solvent environments of three VSE probes containing acetonitrile or fluorine functionalities which have been well-characterized experimentally. Reasonable agreement with the experimentally determined Stark shifts is obtained when the MM atoms are described by the CHARMM additive force field, though it is essential to employ an anharmonic correction in the frequency calculation. In addition, the electric field created by the solvent is computed along the CN bond and a theoretical Stark tuning rate is determined for acetonitrile and shown to be in satisfactory agreement with experiment.

Additive empirical force field for hexopyranose monosaccharides.

We present an all-atom additive empirical force field for the hexopyranose monosaccharide form of glucose and its diastereomers allose, altrose, galactose, gulose, idose, mannose, and talose. The model is developed to be consistent with the CHARMM all-atom biomolecular force fields, and the same parameters are used for all diastereomers, including both the alpha- and beta-anomers of each monosaccharide. The force field is developed in a hierarchical manner and reproduces the gas-phase and condensed-phase properties of small-molecule model compounds corresponding to fragments of pyranose monosaccharides. The resultant parameters are transferred to the full pyranose monosaccharides, and additional parameter development is done to achieve a complete hexopyranose monosaccharide force field. Parametrization target data include vibrational frequencies, crystal geometries, solute-water interaction energies, molecular volumes, heats of vaporization, and conformational energies, including those for over 1800 monosaccharide conformations at the MP2/cc-pVTZ//MP2/6-31G(d) level of theory. Although not targeted during parametrization, free energies of aqueous solvation for the model compounds compare favorably with experimental values. Also well-reproduced are monosaccharide crystal unit cell dimensions and ring pucker, densities of concentrated aqueous glucose systems, and the thermodynamic and dynamic properties of the exocyclic torsion in dilute aqueous systems. The new parameter set expands the CHARMM additive force field to allow for simulation of heterogeneous systems that include hexopyranose monosaccharides in addition to proteins, nucleic acids, and lipids.