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Protein-Specific Charges for Drug Discovery (PSCDD)

ESP error for point charges
Many diseases are associated with abnormal protein behaviour and an effective treatment is often to target proteins and modulate their activity with small therapeutic molecules. Lead optimisation is the process of tuning the properties of a drug candidate to increase binding strength and, hence, inhibitory potency (see right) and it requires an accurate description of the interactions between the drug molecule and its receptor. Computational simulations of these interactions rely on classical molecular mechanics force fields with atom-centred point charges, which are often fit to reproduce quantum mechanical properties of small molecules.

Assignment of AIM densities in myoglobin

Yet recent advances in linear-scaling density functional theory software allow quantum mechanical simulation of biomolecules comprising thousands of atoms. In this ERC-sponsored project, we aim to enhance the accuracy of computational lead optimisation by deriving the point charges of the target receptor directly from a single quantum mechanical simulation of the entire protein, thus incorporating the electrostatic polarisation of the protein's native state into the charge fitting procedure.

(Left) The total QM electron density of a ~1000 atom portion of the myoglobin protein, which is used to store oxygen in muscle tissues. (Inset) The electron density is partitioned into approximately spherical regions using atoms-in-molecule techniques, which allows a set of atom-centred point charges to be assigned to the protein.

ESP error for point charges

The derived charges are chemically intuitive, scale up to very large systems including entire proteins, reproduce the quantum mechanical electrostatic potential (right) and are transferable between closely related systems. Simulated NMR data derived from dynamical simulations of three proteins using molecular mechanics force fields based on these protein-specific charges are in good agreement with experiment.

Ongoing projects are investigating the use of protein-specific charges in the lead optimisation stages of drug development.

Selected Publications:

D. J. Cole, J. Z. Vilseck, J. Tirado-Rives, M. C. Payne, W. L. Jorgensen
Biomolecular Force Field Parameterization via Atoms in Molecule Electron Density Partitioning
Journal of Chemical Theory and Computation, 12, 2312 (2016) Full text

L. P. Lee, N. Gabaldon Limas, D. J. Cole, M. C. Payne, C.-K. Skylaris, T. A. Manz
Expanding the Scope of Density Derived Electrostatic and Chemical Charge Partitioning to Thousands of Atoms
Journal of Chemical Theory and Computation, 10, 5377 (2014) Full text

D. J. Cole, J. Tirado-Rives, W. L. Jorgensen
Molecular Dynamics and Monte Carlo Simulations for Protein-Ligand Binding and Inhibitor Design
Biochimica et Biophysica Acta (BBA) - General Subjects, 1850, 966 (2015) Full text

L. P. Lee, D. J. Cole, C.-K. Skylaris, W. L. Jorgensen, M. C. Payne
Polarized Protein-Specific Charges from Atoms-in-Molecule Electron Density Partitioning
Journal of Chemical Theory and Computation, 9, 2981 (2013) Abstract Full text

Selected Presentations:

"Biomolecular Force Field Parameterization via Atoms in Molecule Electron Density Partitioning"
Lennard-Jones Centre masterclass in computer-aided drug design, Cambridge (2016);
ACS Spring Meeting, San Diego, U.S.A. (2016);
CECAM workshop Beyond point charges: novel electrostatic developments in force fields, Lausanne, Switzerland (2016).

"Enhanced Monte Carlo Sampling through Replica Exchange with Solute Tempering",
2014 Workshop on Free Energy Methods in Drug Design, Boston, U.S.A (2014);
American Chemical Society March Meeting, Dallas, U.S.A. (2014).

"Optimisation of non-nucleoside Inhibitors of HIV-1 Reverse Transcriptase (NNRTIs)",
Schrödinger User Group Meeting, Boston, U.S.A. (2014).

Marie Curie funding

The PSCDD project has received funding from the European Union Seventh Framework Programme through a Marie Curie IOF Action.