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MOLECULAR STRUCTURE FOR OPTIMIZATION IN SITU

SZYBKI/FreeForm

SZYBKI [1] optimizes molecular structures with the force field, either with or without solvent effect, to yield quality 3D molecular structures for use as input to other programs. Since the chemistry of molecular interactions is a matter of shape and electrostatics, it is impossible to consider either without reasonable 3D molecular structures.

SZYBKI/FreeForm
In situ optimization of a ligand with SZYBKI.

Features

  • The ability to perform ligand entropy calculations in different environments[2]
  • The ability to handle certain classes of divalent selenium compounds including selenols (RSeH) and certain specific selenides (RSeR1)
  • Reported ligand RMSD values can now optionally refer to the heavy atoms only
  • Faster calculation of default VdW protein-ligand potential in the active site via the use of lookup tables. Exact VdW protein-ligand potentials can still be calculated if desired
  • Choice of force fields including OpenFF (Open Force Field Initiative) force fields Sage and Parsley, AMBER Protein force fields ff14SB and AMBER99, and the MMFF94 (Merck Molecular Force Field)[2]
  • Solvent effects with ZAP's Poisson-Boltzmann model or the Sheffield model [3] for binding energies and geometry optimization
  • Flexibility of protein active-site polar hydrogens or side-chains
  • Ligand optimization within the field of a protein active site
  • Gradient minimization in several coordinate frames (Cartesian, torsional, rigid body)
  • Fully optimizes (gas phase) about 200 drug-sized molecules per minute
  • Optionally excludes various terms from potential when determining energy and gradient
  • Constrains coordinates (fixed atoms or harmonic constraints)
  • Distributed processing via MPI for all supported platforms
Accurate Poisson—Boltzmann vs. Sheffield Solvation Model solvation energies for a database of 64,000 drug-like molecules [3].
Accurate Poisson—Boltzmann vs. Sheffield Solvation Model solvation energies for a database of 64,000 drug-like molecules [3].

SZYBKI also refines portions of a protein structure and optimizes ligands within a protein active site, making it useful in conjunction with docking programs.

Supported force fields in SZYBKI include OpenFF (Open Force Field Initiative) force fields Sage and Parsley, AMBER Protein force fields ff14SB and AMBER99, and the MMFF94 (Merck Molecular Force Field).

FreeForm is a utility program included with SZYBKI that provides two functionalities: (1) the solvation energy of the free ligand, and (2) the free energy of going from an ensemble of solution phase conformers to a single, bioactive conformation.

For more detailed information on SZYBKI, check out the link below:

Documentation
freeform-conformer-free-energies
FreeForm calculates the Conformer ∆G to adopt the bioactive conformer.

References

  1. Szybki (shib´·kee) means "fast" in Polish.
  2. Ligand entropy in gas-phase, upon solvation and protein complexation. Fast estimation with Quasi-Newton Hessian Wlodek, S., Skillman, A.G., Nicholls, A. J. Chem. Theory Comput., 2010, 6(7), 2140-2152.
  3. Merck molecular force field. I. Basis, form, scope, parameterization, and performance of MMFF94 Halgren, T.A., J. Comp. Chem, 1996, 17, 490. MMFF94s option for energy minimization studies Halgren, T.A., J. Comp. Chem, 1999, 20, 720.
  4. A simple formula for dielectric polarisation energies: The Sheffield Solvation Model Grant, J.A., Pickup, B.T., Sykes, M.J., Kitchen, C.A., Nicholls, A., Chem. Phys. Lett., 2007, 441, 163.

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