Application of Hyper Chem

HyperChem is the PC-based molecular modeling and simulation software package marketed by Hypercube Inc. (http://www.hyper.com). The program provides molecular mechanics (with MM+, AMBER, BIO + (CHARMm), and OPLS force fields), semiempirical (extented Hlickel, CNDO, INDO, MINDO3, MNDO, AM1, PM3, and ZINDO), and ab initio quantum mechanics calculations. Computations are carried out for single-point energy, geometry optimization (energy minimization), molecular dynamics, Langevin dynamics, Monte Carlo simulation, and conforma-tional search. The accompanied manuals should be consulted for various applications of HyperChem.

The HyperChem window displays the menu bar (File, Edit, Build, Select, Display, Databases, Setup, Compute, Annotation, Cancel, and Scipt menus), tool bar (draw, select, display, move and shortcut icons), Workspace, and status line. The program supports various 2D and 3D files including HyperChem (*.hin), PDB (pdb files in .ent), MDL (*.mol), Tripos (*.mlz) files. ISISDraw (*.skc) can also be opened or saved from the File menu. The 2D sketch can be converted into a 3D structure (and calculation of atom types for MM) by selecting Model build from the Build menu. The Build menu also provides tools for building the structure. United atoms tool simplifies a molecular structure and calculations by including hydrogen atoms in the definition of carbon atoms. HyperChem uses atom types for molecular mechanical calculations. The atom types can be calculated (Calculate types) or changed (Set atom type). The Edit menu contains items for manipulating displayed structure while the Display menu determines the appearance of molecules in the workspace (e.g., Show selection, Rendering, Overlay, Show isosurface, Show periodic box, Show multiple bonds, Show hydrogen bonds, Recompute H bonds, add Labels, and change Color). Rendering displays model rendering in sticks (stereo, ribbons, and wedges), balls, balls and cylinders, overlapping spheres, dots, and sticks and dots (Figure 14.7). Two selected molecules can be placed on top of one another by using Overlay tool of the Display menu. The Select menu enables the selection of Atoms, Residues, Molecules, and Spheres that encompasses all atoms within a 3D sphere plus all atoms with/without 2D rectangle.

The Setup and Compute menus contain tools for carrying out chemical calculations. For molecular mechanics energy computation,

• Select atoms or residues to be included in the calculation (default is the whole molecule).

• Choose Start Log command from the File menu if you want to store energy calculations in a log file (chem.log as default).

• Choose force field (MM +, AMBER, BIO + (CHARMm), or OPLS) from the Setup menu.

• Click the Options button to open the option dialog box.

• For MM+ (energy calculations of small biomolecules or ligands): Choose either Bond dipoles or Atomic charges (assigned via Builds Set charge) for use in the calculations of nonbounded Electrostatic interactions. Select None (calculate all nonbonded interactions recommended for small molecules), Switched or Shifted for Cutoffs (for large molecules).

• For AMBER, BIO + , or OPLS (energy calculation of biomacromolecules): Choose Constant (for systems in a gas phase or in an explicit solvent) or Distance dependent (to approximate solvent effects in the absence of an explicit solvent) and set Scale factor for Dielectric permittivity (>1.0 with the default of 1.0 being applicable to most systems). Select either Switched or Shifted for Cutoffs and set Electrostatic (the range is 0 to 1; use 0.5 for

Figure 14.7. Display of molecular structure with HyperChem. Heptapeptide, STANLEY, is displayed in sticks and dots representation. The inset shows the dialog box for rendering options.

AMBER and OPLS, and use 0.4, 0.5, or 1.0 for BIO + ) and van der Waals (the range is 0 to 1; use 0.5 for AMBER, 1.0 for BIO + , and 0.125 for OPLS). Different parameter sets are available for the AMBER force field (AMBER 2, 3, 94, or 96), which can be selected from Setup/Parameter of Force Field options (Figure 14.8).

• After choosing Setup menu options, execute chemical calculations from Compute menu commands to perform one of the followings.

(a) Single point: calculates the total energy and the RMS gradient.

(b) Geometry optimization: executes energy minimization, and calculates an optimum molecular structure with lowest energy and smallest RMS gradient.

(c) Molecular dynamics: calculates the motion of selected atoms over picosecond intervals to search for stable conformations.

(d) Langevin dynamics: calculates the motion of selected atoms over picosecond intervals using frictional effects to simulate the presence of a solvent.

(e) Monte Carlo: calculates ensemble averages for selected atoms.

Additional commands are available for semiempirical and ab initio calculations. These include:

(a) Vibration (calculates the vibrational motions of selected atoms)

(b) Transition state (searches for transition states of reactant or product atoms)

Figure 14.8. Molecular mechanics calculation with HyperChem. Setup for MM calculation of lysozyme (pdbllyz.ent) includes selection of the method and options. The lower left inset displays dialog box for MM methods and the upper right inset shows dialog box for force field options.

(c) Plot molecular properties (displays the electrostatic potential, total spin density or total charge density)

(d) Orbitals (analyzes and displays orbitals and their energy levels)

(e) Vibrational spectrum (analyzes and displays the vibrational frequencies)

(f) Electronic spectrum (analyzes and displays the ultraviolet-visible spectrum)

For energy minimization,

• Select Computer-Geometry optimization to open Molecular mechanics optimization dialog box (Figure 14.9).

• Choose algorithm such as Steepest descent, Fletcher - Reeves (conjugate gradient), or Polak-Ribiere (conjugate gradient, default of HyperChem), and choose options for termination condition such as RMS gradient (e.g., 0.1 kcal/mol Â) or number of maximum cycles.

• Click OK to close the dialog box and start optimization.

To apply periodic boundary conditions for solvation,

• Select Setup r Periodic box to open Periodic box options box.

• Referring to the dimension given for the smallest box enclosing solute, assign the dimension for the Periodic box size (e.g., twice of the largest dimension for

Figure 14.9. Geometry optimization with HyperChem. Setup for geometry optimization includes selection of algorithm and options. The inset shows the dialog box for these selections. Initially, in vacuo condition is chosen.

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Figure 14.9. Geometry optimization with HyperChem. Setup for geometry optimization includes selection of algorithm and options. The inset shows the dialog box for these selections. Initially, in vacuo condition is chosen.

the given smallest box or a cube of 18.70 A on the side recommended by HyperChem but not exceeding 56.10 A on the side), maximum number of water molecules (for information), and minimum distance between solvent and solute atoms (practical range: 1 -5 with the default of 2.3 A).

• Click OK to close the option box and start optimization.

For molecular dynamics calculation,

• Select Computer-Molecular dynamics to open Molecular dynamics options dialog box.

• Set heat time (e.g., 5 ps), run time (at equilibrium, e.g. 5 ps), step size (e.g., 0.005 ps), starting temperature (e.g., 0 K), simulation or final temperature (e.g., 300 K), and temperature step (e.g., 30 K).

• Choose In vacuo (for the system not in a periodic box) or Periodic boundary conditions (for the system in a defined periodic box),

• Set Bath relaxation time (suggested range: step size to the default of 0.1 ps) and assign any number between — 32,768 and 32,768 for Random seed as the starting point for the random number generator used for the simulations. Friction coefficient (any positive value) is needed only for the Langevin dynamics.

• Click the Snapshots button if you want playback of MolD trajectories (saved in a movie file .avi).

Figure 14.10. Molecular dynamics with HyperChem. Setup for MD under periodic boundary conditions includes defining the periodic boundary box, selecting molecular dynamics options, and setting dynamics average output. The setup for Langevin dynamics of heptapeptide (STANLEY) is illustrated (note that the periodic boundary conditions radio is checked). The upper right inset shows the dialog box for Langevin dynamics options, and the lower left dialog box depicts the dialog box (opened by clicking Average button of the MD options dialog box) for dynamics average output. Molecular dynamics calculation is initiated by clicking Proceed button of the MD options dialog box.

Figure 14.10. Molecular dynamics with HyperChem. Setup for MD under periodic boundary conditions includes defining the periodic boundary box, selecting molecular dynamics options, and setting dynamics average output. The setup for Langevin dynamics of heptapeptide (STANLEY) is illustrated (note that the periodic boundary conditions radio is checked). The upper right inset shows the dialog box for Langevin dynamics options, and the lower left dialog box depicts the dialog box (opened by clicking Average button of the MD options dialog box) for dynamics average output. Molecular dynamics calculation is initiated by clicking Proceed button of the MD options dialog box.

• Click the Average button to select average values of kinetic energy (EKIN), potential energy (EPOT), total energy (ETOT), and their RMS deviations and named selections (user selected interatomic distances, angles or torsion angles) to save (default, chem.csv) and plot after the simulation.

• Analogous procedures are applied to the Langevin dynamics (via Compute^ Langevin dynamics) as shown in Figure 14.10 and Monte Carlo simulation (via Compute^Monte Carlo).

The biopolymer modeling of HyperChem includes Building polynucleotides, polypeptides and polysaccharides, Amino acid sequence (fasta format) editing, Mutations, Overlapping by RMS fit, and Merging structures. To facilitate manipulation of protein structures, there is often a need to display the protein backbone only as follows.

• Set the select level to Molecule and use selection tool to click on the protein molecule.

• Change the selection to water molecules by choosing Complement selection on the Select menu.

• Choose Clear command on the Edit menu to remove water molecules and to display the protein structure.

• Turn off Show Hydrogens on the Display menu.

• Choose Select Backbone on the Select menu and the Show Selection Only on the Display menu to display the backbone of the polypeptide chain.

The Databases menu provides tools for building polypeptides (Amino Acids, Make Zwitterion, Sequence Editor), polynucleotides (Nucleic Acids), polysaccharides (Saccharides), and organic polymers (Polymers) from residues (monomer units) as exemplified for DNA in Figure 14.11.

To build protein structure,

• Select Amino Acids from the Databases menu to open the amino acid dialog box.

Figure 14.11. Construction of biopolymer with HyperChem. Two menus are available for creating 3D structure models in HyperChem. The Build menu provides tools for creating organic molecules. Use the Drawing tool to sketch atoms in a molecule and connect them with covalent bonds. Invoke the Model builder to create a 3D structure from the 2D sketch. The Databases menu offers tools for creating biopolymers from residues with user specified linkages and conformations—that is, polysaccharides from monosaccharides, polypeptides form amino acids, and polynucleotides from nucleotides. A double-stranded DNA chain, for example, is constructed from nucleotide residues in a desired conformation (the inset).

Figure 14.11. Construction of biopolymer with HyperChem. Two menus are available for creating 3D structure models in HyperChem. The Build menu provides tools for creating organic molecules. Use the Drawing tool to sketch atoms in a molecule and connect them with covalent bonds. Invoke the Model builder to create a 3D structure from the 2D sketch. The Databases menu offers tools for creating biopolymers from residues with user specified linkages and conformations—that is, polysaccharides from monosaccharides, polypeptides form amino acids, and polynucleotides from nucleotides. A double-stranded DNA chain, for example, is constructed from nucleotide residues in a desired conformation (the inset).

• Choose chain conformation (Alpha Helix or Beta Sheet or Other) and isomer (l or d), and pick amino acids from the N-terminus.

• Close the dialog box to complete the chain.

To construct nucleic acids,

• Choose Nucleic Acids on the Databases menu.

• From the dialog box, choose the helical conformation of nucleic acid (A, B, Z, or other form) and add nucleotides (dA, dT, dG, and dC for DNA; rA, rU, rG, and rC for RNA) in the direction of 5' to 3' (default) or a choice of Backward and Double stranded. Both termini can be capped (5' Cap and 3' Cap).

To construct polysaccharides,

• Select Saccharide from the Display menu to open the Sugar builder window.

• Choose Add menu from the Sugar builder window to open the dialog box for linking monosaccharides (Aldoses, Ketoses, Derivatives, or End groups).

• Each selection opens another dialog box with options for choosing specific saccharide residues in pyranose or furanose forms, anomer (a, p, or acyclic), isomer (d or l), and type of link (linkage type).

• Add (pick) saccharide residues from the list of aldoses (hexoses in al-dopyranose form, pentoses in aldofuranose form, and tetraoses in open-chain form), ketoses (hexoses in ketofuranose form, pentoses and tetraose in open-chain form), derivatives (glucosamine, galactosamine, N-acetylnuraminic acid, N-acetyl muramic acid, inositol, 2-deoxyribose, rhamnose, fucose, and apiose), and blocking groups (H, NH2, =O, COO—, methyl, lactyl, O-methyl, N-methyl, O-acetyl, N-acetyl, phosphoric acid, sulfate, N-sulfonic acid) to build polysaccharides.

The Databases menu also permits the mutation of the selected amino acid residue(s) of a protein molecule. Choose Mutate from the Database menu to open a listing of amino acids. Highlighting the candidate amino acid effects the mutation.

To compare structures of two molecules by overlapping,

• Open the first molecule.

• Choose Merge command from the File menu to open the second molecule.

• Set different colors for the two structures (DisplaysColor after selecting the molecule).

• Select matching residue (s) from each of the two molecules via Selects Residues Select to open a dialog box.

• Enter residue number under By number/Residue number. (Repeat the process in order to use more than one residue for the overlaying.)

• Choose RMS Fit and Overlay on the Display menu and pick the desired overlaying option (Molecular numbering or Selection order). This places one molecule on top of another (Figure 14.12).

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|U h.-Li i - I PF+" -H " -IJ-V.. "-"iH M-

Figure 14.12. Superimposition of molecular structures with HyperChem. Pigeon lyso-zyme structure (red) derived from homology modeling with Swiss-PDB Viewer is overlapped against chicken lysozyme structure, pdbllyz.ent (black). Two catalytic residues, Glu35 and Asp 52 (chicken lysozyme), are highlighted (green).

Figure 14.12. Superimposition of molecular structures with HyperChem. Pigeon lyso-zyme structure (red) derived from homology modeling with Swiss-PDB Viewer is overlapped against chicken lysozyme structure, pdbllyz.ent (black). Two catalytic residues, Glu35 and Asp 52 (chicken lysozyme), are highlighted (green).

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