CHARMM-GUI: a web-based graphical user interface for CHARMM

CHARMM is an academic research program used widely for macromolecular mechanics and dynamics with versatile analysis and manipulation tools of atomic coordinates and dynamics trajectories. CHARMM-GUI, http://www.charmm-gui.org, has been developed to provide a web-based graphical user interface to generate various input files and molecular systems to facilitate and standardize the usage of common and advanced simulation techniques in CHARMM. The web environment provides an ideal platform to build and validate a molecular model system in an interactive fashion such that, if a problem is found through visual inspection, one can go back to the previous setup and regenerate the whole system again. In this article, we describe the currently available functional modules of CHARMM-GUI Input Generator that form a basis for the advanced simulation techniques. Future directions of the CHARMM-GUI development project are also discussed briefly together with other features in the CHARMM-GUI website, such as Archive and Movie Gallery.     

CHARMM: A program for macromolecular energy,minimization, and dynamics calculations

CHARMM (Chemistry at HARvard Macromolecular Mechanics) is a highly flexible computer program which uses empirical energy functions to model macromolecular systems. The program can read or model build structures, energy minimize them by first- or second-derivative techniques, perform a normal mode or molecular dynamics simulation, and analyze the structural, equilibrium, and dynamic properties determined in these calculations. The operations that CHARMM can perform are described, and some implementation details are given. A set of parameters for the empirical energy function and a sample run are included.     

Structure-based ligand design for flexible proteins: Application of new F-DycoBlock

A method of structure-based ligand design – DycoBlock – has been proposed and tested by Liu et al.[1]. It was further improved by Zhu et al. and applied to design new selective inhibitors of cyclooxygenase 2 [2]. In the current work, we present a new methodology – F-DycoBlock that allows for the incorporation of receptor flexibility. During the designing procedure, both the receptor and molecular building blocks are subjected to the multiple-copy stochastic molecular dynamics (MCSMD) simulation [1], while the protein moves in the mean field of all copies. It is tested for two enzymes studied previously – cyclooxygenase 2 (COX-2) and human immunodeficiency type 1 (HIV-1) protease. To identify the applicability of F-DycoBlock, the binding protein structure was used as starting point to explore the conformational space around the bound state. This method can be easily extended to accommodate the flexibility in different degree. Four types of treatment of the receptor flexibility – all-atom restrained, backbone restrained, intramolecular hydrogen-bond restrained and active-site flexible – were tested with or without the grid approximation. Two inhibitors, SC-558 for COX-2 and L700417 for HIV-1 protease, are used in this testing study for comparison with previous results. The accuracy of recovery, binding energy, solvent accessible surface area (SASA) and positional root-mean-square (RMS) deviation are used as criteria. The results indicate that F-DycoBlock is a robust methodology for flexible drug design. It is particularly notable that the protein flexibility has been perfectly associated with each stage of drug design – search for the binding sites, dynamic assembly and optimization of candidate compounds. When all protein atoms were restrained, F-DycoBlock yielded higher accuracy of recovery than DycoBlock (100%). If backbone atoms were restrained, the same ratio of accuracy was achieved. Moreover, with the intramolecular hydrogen bonds restrained, reasonable conformational changes were observed for HIV-1 protease during the long-time MCSMD simulation and L700417 was reassembled at the active site. It makes it possible to study the receptor motion in the binding process.     

A truncated Newton minimizer adapted for CHARMM and biomolecular applications

We report the adaptation of the truncated Newton minimization package TNPACK for CHARMM and biomolecular energy minimization. TNPACK is based on the preconditioned linear conjugate–gradient technique for solving the Newton equations. The structure of the problem—sparsity of the Hessian—is exploited for preconditioning. Experience with the new version of TNPACK is presented on a series of molecular systems of biological and numerical interest: alanine dipeptide (N-methyl-alanyl-acetamide), a dimer of N-methyl-acetamide, deca-alanine, mellitin (26 residues), avian pancreatic polypeptide (36 residues), rubredoxin (52 residues), bovine pancreatic trypsin inhibitor (58 residues), a dimer of insulin (99 residues), and lysozyme (130 residues). Detailed comparisons among the minimization algorithms available in CHARMM, particularly those used for large-scale problems, are presented along with new mathematical developments in TNPACK. The new TNPACK version performs significantly better than ABNR, the most competitive minimizer in CHARMM, for all systems tested in terms of CPU time when curvature information (Hessian/vector product) is calculated by a finite-difference of gradients (the numeric option of TNPACK). The remaining derivative quantities are, however, evaluated analytically in TNPACK. The CPU gain is 50% or more (speedup factors of 1.5 to 2.5) for the largest molecular systems tested and even greater for smaller systems (CPU factors of 1 to 4 for small systems and 1 to 5 for medium systems). TNPACK uses curvature information to escape from undesired configurational regions and to ensure the identification of true local minima. It converges rapidly once a convex region is reached and achieves very low final gradient norms, such as of order 10^?8, with little additional work. Even greater overall CPU gains are expected for large-scale minimization problems by making the architectures of CHARMM and TNPACK more compatible with respect to the second-derivative calculations. © 1994 by John Wiley & Sons, Inc.     

CHARMM general force field: A force field for drug‐like molecules compatible with the CHARMM all‐atom additive biological force fields

The widely used CHARMM additive all‐atom force field includes parameters for proteins, nucleic acids, lipids, and carbohydrates. In the present article, an extension of the CHARMM force field to drug‐like molecules is presented. The resulting CHARMM General Force Field (CGenFF) covers a wide range of chemical groups present in biomolecules and drug‐like molecules, including a large number of heterocyclic scaffolds. The parametrization philosophy behind the force field focuses on quality at the expense of transferability, with the implementation concentrating on an extensible force field. Statistics related to the quality of the parametrization with a focus on experimental validation are presented. Additionally, the parametrization procedure, described fully in the present article in the context of the model systems, pyrrolidine, and 3‐phenoxymethylpyrrolidine will allow users to readily extend the force field to chemical groups that are not explicitly covered in the force field as well as add functional groups to and link together molecules already available in the force field. CGenFF thus makes it possible to perform “all‐CHARMM” simulations on drug‐target interactions thereby extending the utility of CHARMM force fields to medicinally relevant systems. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2010     

Salicylaldiminato derivatives of cyclotriveratrylene: flexible strategy for new rim-metalated CTV complexes

The amino-derivatized cyclotriveratrylene analogue, triaminotrimethoxytribenzocyclononene [CTV(NH2)3(OMe)3], 1, is readily converted into triply substituted imine compounds [CTV(sal)3(OMe)3], 2, in high yield by treatment of the acid salt of 1 with a variety of substituted salicylaldehydes. Cleavage of the protecting methoxy group generates the tristridentate chelate CTV(sal)3(OH)3, 3, which is readily converted into new rim-metalated species CTV(sal)3(ONiL)3, 4a (a, L = pyrrolidine; b, L = 1-n-butyl-imidazole). Taken together, these results illustrate the remarkable synthetic flexibility that is possible for the CTV-based metal complexes by alteration of the metal, the salicylaldehyde component of the CTV ligand, or the ancillary ligands coordinated to the metal.     

Monte Carlo simulations of biomolecules: The MC module in CHARMM

We describe the implementation of a general and flexible Monte Carlo (MC) module for the program CHARMM, which is used widely for modeling biomolecular systems with empirical energy functions. Construction and use of an almost arbitrary move set with only a few commands is made possible by providing several predefined types of moves that can be combined. Sampling can be enhanced by noncanonical acceptance criteria, automatic optimization of step sizes, and energy minimization. A systematic procedure for improving MC move sets is introduced and applied to simulations of two peptides. The resulting move sets allow MC to sample the configuration spaces of these systems much more rapidly than Langevin dynamics. The rate of convergence of the difference in free energy between ethane and methanol in explicit solvent is also examined, and comparable performances are observed for MC and the Nosé-Hoover algorithm. Its ease of use combined with its sampling efficiency make the MC module in CHARMM an attractive alternative for exploring the behavior of biomolecular systems.     

Modification of the CHARMM force field for DMPC lipid bilayer

The CHARMM force field for DMPC lipids was modified in order to improve agreement with experiment for a number of important properties of hydrated lipid bilayer. The modification consists in introduction of a scaling factor 0.83 for 1-4 electrostatic interactions (between atoms separated by three covalent bonds), which provides correct transgauche ratio in the alkane tails, and recalculation of the headgroup charges on the basis of HF/6-311(d,p) ab-initio computations. Both rigid TIP3P and flexible SPC water models were used with the new lipid model, showing similar results. The new model in a 75 ns simulation has shown a correct value of the area per lipid at zero surface tension, as well as good agreement with the experiment for the electron density, structure factor, and order parameters, including those in the headgroup part of lipids.     

Optimization of CHARMM force field parameters for the chalcone fragment

In this work,we developed the CHARMM all-atom force field parameters for the nonstandard biological residue chalcone,followed by the standard protocol for the CHARMM27 force field development.Target data were generated via ab initio calculations at the MP2/6-31G* and HF/6-31G* levels.The reference data included interaction energies between water and the model compound F(a fragment of chalcone).Bond,angle,and torsion parameters were derived from the ab initio calculations and renormalized to maintain compatibility with the existing CHARMM27 parameters of standard residues.The optimized CHARMM parameters perform well in reproducing the target data.We expect that the extension of the CHARMM27 force field parameters for chalcone will facilitate the molecular simulation studies of the reaction mechanism of intramolecular cyclization of chalcone catalyzed by chalcone isomerase.     

A flexible route to new spirodioxanes, oxathianes, and morpholines

This work describes a modular efficient route to 10-aza-4-thia-, 10-aza-4-oxa-, and 10-oxa-4-thia-1,7-dioxaspiro[5.5]undecanes. The synthetic pathway relies upon the iterative nucleophilic substitution of 1,3-dichloropropan-2-one O-benzyloxime by solketal derivatives. The oxime key-intermediates, submitted to an acidic deprotection-spiroacetalization process, afforded these original spiroketal compounds in three steps, few purifications, and very good yields.     

cEST: a flexible tool for calorimetric data analysis

Journal of Thermal Analysis and Calorimetry - The pyrolysis characteristics and kinetics of lignocellulosic biomass (cotton stalk) and seaweed (Gracilaria lemaneiformis) were studied comparatively....     

FFParam: Standalone package for CHARMM additive and Drude polarizable force field parametrization of small molecules

Accurate force-field (FF) parameters are key to reliable prediction of properties obtained from molecular modeling (MM) and molecular dynamics (MD) simulations. With ever-widening applicability of MD simulations, robust parameters need to be generated for a wider range of chemical species. The CHARMM General Force Field program (CGenFF, https://cgenff.umaryland.edu/ ) is a tool for obtaining initial parameters for a given small molecule based on analogy with the available CGenFF parameters. However, improvement of these parameters is often required and performing their optimization remains tedious and time consuming. In addition, tools for optimization of small molecule parameters in the context of the Drude polarizable FF are not yet available. To overcome these issues, the FFParam package has been designed to facilitate the parametrization process. The package includes a graphical user interface (GUI) created using Qt libraries. FFParam supports Gaussian and Psi4 for performing quantum mechanical calculations and CHARMM and OpenMM for MM calculations. A Monte Carlo simulated annealing (MCSA) algorithm has been implemented for automated fitting of partial atomic charge, atomic polarizabilities and Thole scale parameters. The LSFITPAR program is called for automated fitting of bonded parameters. Accordingly, FFParam provides all the features required for generation and analysis of CHARMM and Drude FF parameters for small molecules. FFParam-GUI includes a text editor, graph plotter, molecular visualization, and text to table converter to meet various requirements of the parametrization process. It is anticipated that FFParam will facilitate wider use of CGenFF as well as promote future use of the Drude polarizable FF.     

Aminomethyl-bipyridine bearing two flexible nitronyl-nitroxide arms: a new podand for complexation of transition metals in a facial or meridional conformation

Transition metal complexes of 6-aminomethyl-bis[methyl-2-(4,5-dihydro-4,4,5,5- tetramethylimidazolinyl-3-oxide-l-oxy)]-2,2'-bipyridine, bpyN(NIT)(2), 1, have been synthesized and characterized by FAB-MS, UV-vis, FT-IR, and EPR spectroscopies, elemental analysis, and susceptibility measurements. Single-crystal X-ray diffraction studies have been performed on all compounds giving the following crystal data: bpyN(NIT)(2), 1, triclinic, P(-)1, Z = 2, a = 10.7224(4) A, b = 11.0995(4) A, c = 13.1134(3) A, alpha = 114.101(9) degrees, beta = 97.476(9) degrees, gamma = 99.667(9) degrees; ZnbpyN(NIT)(2), 2, hexagonal, P3(2), Z = 3, a = 15.4545(3) A, b = 15.4545(3) A, c = 13.5594(3) A; NibpyN(NIT)(2), 3, hexagonal, P3(2), Z = 3, a = 15.2867(1) A, b = 15.2867(1) A, c = 13.7160(1) A; CubpyN(NIT)(2), 4, triclinic, P(-)l, Z = 2, a = 11.8640(4) A, b = 13.2023(4) A, c = 13.2661(5) A, alpha = 90.539(9) degrees, beta = 104.983(9) degrees, gamma = 113.252(9) degrees. The two radicals of the free ligand 1 are almost perpendicular to one another in the solid state, favoring a weak ferromagnetic interaction (J/k(B) = 8.8 K). The complexes obtained by wrapping the ligand around a single metal center gave rise to two different coordination schemes where the two radicals of 1 adopt a ON(3)O meridional (with Ni and Zn) or a ON(3)O facial conformation (with Cu), which strongly affects the magnetic and electronic properties (O accounts for the coordinated oxygen atoms of the nitroxide radicals and N(3) accounts for the tertiary amine). For 2, a model of a dimer has been used giving rise to a weak antiferromagnetic interaction between the radicals (J/k(B) = -5.3 K). For 3, a very strong intramolecular antiferromagnetic coupling has been found and estimated at J/k(B) = -230 K and J'/k(B) = -110 K between the nickel and each radical using an asymmetric model of a trimer. For 4, an unusual magnetic behavior is observed, dominated by antiferromagnetic interactions with a residual plateau at chiT = 0.63 emu.K.mol(-)(1). Molecular modeling at the CASSCF level is in keeping with an antiferromagnetic coupling of the radical bound with the Cu(II) in the equatorial position. The combined structural, electronic, and magnetic characteristics suggest that the use of a flexible molecule provide an additional approach for fine-tuning magnetic interactions.     

A flexible porphyrin-annulene hybrid: a nonporphyrin conformation for meso-tetraaryldivacataporphyrin

An annulene–porphyrin hybrid, the diaaza‐deficient porphyrin 5,10,15,20‐tetraaryl‐21,23‐divacataporphyrin, has been synthesized by an extrusion of tellurium atom(s) from 5,10,15,20‐tetraaryl‐21,23‐ditelluraporphyrin under treatment with HCl. In addition, a monoaza‐deficient 5,10,15,20‐tetraaryl‐21‐tellura‐23‐vacataporphyrin was formed in the same reaction. The two new members of the vacataporphyrin family were characterized by X‐ray crystallography, as well as UV/Vis and NMR spectroscopy. These aromatic molecules preserve the fundamental structural and spectroscopic features of the parent tetraarylporphyrin. The X‐ray crystal structures of 21,23‐divacataporphyrin and 21‐tellura‐23‐vacataporphyrin show typical porphyrin patterns. The molecules are not strictly planar and show distortion of the annulene moieties. The N22???N24 distances (5.23 and 5.09 Å) are considerably longer than in regular porphyrins. For 21,23‐divacataporphyrin, variable‐temperature ¹H NMR spectroscopy data allowed the identification of divacataporphyrin stereoisomers differentiated by the geometry of the butadiene bridges. The forms remain in thermodynamic equilibrium.     

CHARMM fluctuating charge force field for proteins: I parameterization and application to bulk organic liquid simulations

A first-generation fluctuating charge (FQ) force field to be ultimately applied for protein simulations is presented. The electrostatic model parameters, the atomic hardnesses, and electronegativities, are parameterized by fitting to DFT-based charge responses of small molecules perturbed by a dipolar probe mimicking a water dipole. The nonbonded parameters for atoms based on the CHARMM atom-typing scheme are determined via simultaneously optimizing vacuum water-solute geometries and energies (for a set of small organic molecules) and condensed phase properties (densities and vaporization enthalpies) for pure bulk liquids. Vacuum solute-water geometries, specifically hydrogen bond distances, are fit to 0.19 A r.m.s. error, while dimerization energies are fit to 0.98 kcal/mol r.m.s. error. Properties of the liquids studied include bulk liquid structure and polarization. The FQ model does indeed show a condensed phase effect in the shifting of molecular dipole moments to higher values relative to the gas phase. The FQ liquids also appear to be more strongly associated, in the case of hydrogen bonding liquids, due to the enhanced dipolar interactions as evidenced by shifts toward lower energies in pair energy distributions. We present results from a short simulation of NMA in bulk TIP4P-FQ water as a step towards simulating solvated peptide/protein systems. As expected, there is a nontrivial dipole moment enhancement of the NMA (although the quantitative accuracy is difficult to assess). Furthermore, the distribution of dipole moments of water molecules in the vicinity of the solutes is shifted towards larger values by 0.1-0.2 Debye in keeping with previously reported work.     

GROMACS: fast, flexible, and free

This article describes the software suite GROMACS (Groningen MAchine for Chemical Simulation) that was developed at the University of Groningen, The Netherlands, in the early 1990s. The software, written in ANSI C, originates from a parallel hardware project, and is well suited for parallelization on processor clusters. By careful optimization of neighbor searching and of inner loop performance, GROMACS is a very fast program for molecular dynamics simulation. It does not have a force field of its own, but is compatible with GROMOS, OPLS, AMBER, and ENCAD force fields. In addition, it can handle polarizable shell models and flexible constraints. The program is versatile, as force routines can be added by the user, tabulated functions can be specified, and analyses can be easily customized. Nonequilibrium dynamics and free energy determinations are incorporated. Interfaces with popular quantum-chemical packages (MOPAC, GAMES-UK, GAUSSIAN) are provided to perform mixed MM/QM simulations. The package includes about 100 utility and analysis programs. GROMACS is in the public domain and distributed (with source code and documentation) under the GNU General Public License. It is maintained by a group of developers from the Universities of Groningen, Uppsala, and Stockholm, and the Max Planck Institute for Polymer Research in Mainz. Its Web site is http://www.gromacs.org.     

Hydrothermal syntheses,crystal structures,and properties of two new coordination polymers constructed from a flexible pyridinecarboxylate ligand

Two new coordination polymers with the same topological structure [Zn(L)]_2n·n(H₂O) (1) and [Co(L)]_2n·n(H₂O) (2) (H₂L = 5-(pyridin-2-ylmethoxy)-isophthalic acid) have been hydrothermally synthesized by reactions of metal salts and H₂L. Single-crystal X-ray analyses reveal that 1 and 2 are isostructural and crystallize in orthorhombic chiral P2₁2₁2 space group. These compounds feature 2-D undulated layer structures with (3,6)-connected kgd topology, which further extended into a 3-D supramolecular framework via intermolecular hydrogen bonds. In addition, the luminescent properties of 1 and 2 and the magnetic property of 2 were also investigated.     

Synthesis of a family of heterocyclic ligands derived from bisphenols: new flexible bridging ligands for use in metallosupramolecular chemistry

The preparations are described of 35 new bridging ligands from five bisphenols through coupling each with seven different heterocyclic units. X-ray crystal structures of five representative examples revealed different conformations in the solid state with the terminal nitrogen donors being separated by distances ranging from 8 to 23 Å.