CEITEC_logo_pos 1 ACC II: Calculation of partial atomic charges Radka Svobodová CEITEC MASARYK UNIVERSITY CEITEC_logo_pos Partial atomic charges 2 Real numbers describing distribution of electron density among atoms. CEITEC_logo_pos 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 CEITEC_logo_pos 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. CEITEC_logo_pos 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 CEITEC_logo_pos 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 CEITEC_logo_pos 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 CEITEC_logo_pos Empirical charge calculation approaches 8 CEITEC_logo_pos Empirical charge calculation approaches 9 CEITEC_logo_pos Electronegativity Equalization Method (EEM): 10 CEITEC_logo_pos 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 CEITEC_logo_pos ACC II: empirical methods included 12 CEITEC_logo_pos 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 CEITEC_logo_pos ACC II: visualization 14 balls and sticks cartoon surface CEITEC_logo_pos ACC II example 1: phenols 15 Partial atomic charges in propofol. The phenol hydrogen is marked with a blue arrow. The partial atomic charges were calculated by EEM. 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. CEITEC_logo_pos 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. CEITEC_logo_pos 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 A picture containing basketball, game Description automatically generated CEITEC_logo_pos ACC II: How to use ACC II? Molnupiravir 18 §Download 3D structure from PubChem §Upload to ACC II §Press Compute charges § § CEITEC_logo_pos ACC II: How to use ACC II? Molnupiravir 19 CEITEC_logo_pos ACC II: How to use ACC II? Molnupiravir 20 CEITEC_logo_pos 21 ACC II: How to use ACC II? CEITEC_logo_pos 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: web-based tool for the calculation of partial atomic charges. Nucleic acids research, 48(W1), pp.W591-W596. Users: 300 unique users / year 5000 computations CEITEC_logo_pos 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 § PDBe home < EMBL-EBI CEITEC_logo_pos 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 MetaCentrum NGI ceitec_PPT_podklad_uvod CEITEC_logo_pos_RGB OPVaVpI_loga-eu_pos_H_EN partner_logo_2_col 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