1 ACC II: Calculation of partial atomic charges Radka Svobodová CEITEC MASARYK UNIVERSITY Partial atomic charges 2 Real numbers describing distribution of electron density among atoms. Application of partial atomic charges 3 Application fields: ▪ Organic chemistry ▪ Physical chemistry ▪ Computational chemistry ▪ Chemoinformatics ▪ Bioinformatics ▪ Nanoscience Applications: ▪ Prediction of electrostatic interactions ▪ Molecular mechanics and dynamics ▪ Docking ▪ Virtual screening ▪ QSAR/QSPR modeling ▪ Prediction of bonding sites ▪ Similarity search How to obtain charges? 4 Partial atomic charges = a theoretical concept We cannot measure them! We can only compute them. Consequences: ▪ Many different charge calculation approaches were developed ▪ We cannot select the best approach Validation: We can calculate somethig mesurable from them. Charge calculation approaches 5 Quantum mechanical methods Advantages: ▪ Calculated ab-initio ▪ High quality charges Disadvantages: ▪ Computationally expensive ▪ Complexity from O(E3) to O(E6), where E is a number of electrons ▪ Cannot be used for macromolecules Charge calculation approaches 6 Quantum mechanical methods Advantages: ▪ Calculated ab-initio ▪ High quality charges Disadvantages: ▪ Computationally expensive ▪ Complexity from ▪ O(E3) to O(E6), where E is a number of electrons ▪ Cannot be used for macromolecules Empirical methods Advantages: ▪ Fast calculation ▪ Complexity O(N3), where N is a number of atoms Disadvantages: ▪ Fitted to QM charges ▪ Necessity of parameterization – not easy Empirical charge calculation approaches 7 Conformationally independent (2D): ▪ Based on molecular 2D structure ▪ Does not reflect conformational changes Conformationally dependent (3D): ▪ Based on molecular 3D structure ▪ Different conformation ~ different charges BK channel closed BK channel open Empirical charge calculation approaches 8 Empirical charge calculation approaches 9 Electronegativity Equalization Method (EEM): 10 Atomic Charge Calculator II (ACC II) 11 ▪ Includes 20 empirical charge calculation methods ▪ Inputs: SDF, MOL2, PDB, mmcif or archive with these files ▪ Outputs: plain text, Mol2, PQR ▪ Visualization: LiteMol plugin ▪ Web page: https://acc2.ncbr.muni.cz ▪ Command line application available ACC II: empirical methods included 12 ACC II: workflow 13 ▪ Uploading the structure(s) ▪ Internal validation ▪ Selecting the empirical method and its parameter set ▪ Executing the selected method: ▪ If large molecules, the Cutoff or Cover approaches are used ▪ Visualizing the computed charges ACC II: visualization 14 balls and sticks cartoon surface ACC II example 1: phenols 15 Partial atomic charges in propofol. The phenol hydrogen is marked with a blue arrow. Svobodová, R., Geidl, S., Ionescu, C.M., Skřehota, O., Bouchal, T., Sehnal, D., Abagyan, R. and Koča, J., 2013. Predicting p K a values from EEM atomic charges. Journal of cheminformatics, 5(1), pp.1-15. ACC II example 2: apoptotic protein BAX 16 (A) Inactive BAX (PDB ID 1f16). (B) Activated BAX (PDB ID 2k7w). An activator is marked with a blue oval, the C domain is marked with a green oval. The C domain of activated BAX is depolarized – it is mainly white or whitish in colour. This depolarization causes the C domain to be released and penetrate the mitochondrial membrane and initiate apoptosis. ACC II example 3: membrane protein 17 Structure of nicotinic acetylcholine receptor (PDB ID 2bg9). Nonpolar transmembrane part and polar surface of extracellular and cytoplasmic parts ACC II: How to use ACC II? Molnupiravir 18 ▪ Download 3D structure from PubChem ▪ Upload to ACC II ▪ Press Compute charges ACC II: How to use ACC II? Molnupiravir 19 ACC II: How to use ACC II? Molnupiravir 20 21 ACC II: How to use ACC II? Atomic Charge Calculator II Impact 22 Publications: ▪ Ionescu, C.M., Sehnal, D., Falginella, F.L., Pant, P., Pravda, L., Bouchal, T., Svobodová, R., Geidl, S. and Koča, J., 2015. AtomicChargeCalculator: interactive web-based calculation of atomic charges in large biomolecular complexes and drug-like molecules. Journal of cheminformatics, 7(1), pp.1-13. ▪ Raček, T., Schindler, O., Toušek, D., Horský, V., Berka, K., Koča, J. and Svobodová, R., 2020. Atomic Charge Calculator II: webbased tool for the calculation of partial atomic charges. Nucleic acids research, 48(W1), pp.W591-W596. Users: 300 unique users / year 5000 computations Atomic Charge Calculator II Future plans 23 ▪ Develop methodology, covering whole PDB ▪ Automatic adding of hydrogens ▪ Prediction of total charge based on pH ▪ Integrate into PDBe-KB and PDBe ELIXIR and ELIXIR CZ MetaCenter EMBL-EBI, PDBe: Dr. Sameer Velankar Acknowledgement 24 Jaroslav Koča Tomáš Raček, Ondřej Schindler, Vladimír Horský David Sehnal, Stanislav Geidl, Crina-Maria Ionescu Aleksandra Maršavelski Karel Berka Central European Institute of Technology Masaryk University Kamenice 753/5 625 00 Brno, Czech Republic www.ceitec.muni.cz | info@ceitec.muni.cz Thank you for your attention