The AlphaFold2 prediction algorithm opened up the possibility of exploring proteins' structural space at an unprecedented scale. Currently, >200 million protein structures predicted by this approach are deposited in AlphaFoldDB, covering entire proteomes of multiple organisms, including humans. Predicted structures are, however, stored without detailed functional annotations describing their chemical behaviour. Partial atomic charges, which map electron distribution over a molecule and provide a clue to its chemical reactivity, are an important example of such data. We introduce the web application αCharges: a tool for the quick calculation of partial atomic charges for protein structures from AlphaFoldDB. The charges are calculated by the recent empirical method SQE+qp, parameterised for this class of molecules using robust quantum mechanics charges (B3LYP/6-31G*/NPA) on PROPKA3 protonated structures. The computed partial atomic charges can be downloaded in common data formats or visualised via the powerful Mol* viewer. The αCharges application is freely available at https://alphacharges.ncbr.muni.cz with no login requirement.

CEITEC Central European Institute of Technology Masaryk University 625 00 Brno Czech Republic

Department of Physical Chemistry Faculty of Science Palacký University Olomouc 779 00 Olomouc Czech Republic

Faculty of Informatics Masaryk University 602 00 Brno Czech Republic

Institute of Computer Science Masaryk University 602 00 Brno Czech Republic

National Centre for Biomolecular Research Faculty of Science Masaryk University 625 00 Brno Czech Republic

Zobrazit více v PubMed

Jumper J., Evans R., Pritzel A., Green T., Figurnov M., Ronneberger O., Tunyasuvunakool K., Bates R., Žídek A., Potapenko A.et al. .. Highly accurate protein structure prediction with AlphaFold. Nature. 2021; 596:583–589. PubMed PMC

Varadi M., Anyango S., Appasamy S.D., Armstrong D., Bage M., Berrisford J., Choudhary P., Bertoni D., Deshpande M., Leines G.D.et al. .. PDBe and PDBe-KB: providing high-quality, up-to-date and integrated resources of macromolecular structures to support basic and applied research and education. Protein Sci. 2022; 31:e4439. PubMed PMC

Varadi M., Anyango S., Deshpande M., Nair S., Natassia C., Yordanova G., Yuan D., Stroe O., Wood G., Laydon A.et al. .. AlphaFold Protein Structure Database: massively expanding the structural coverage of protein-sequence space with high-accuracy models. Nucleic Acids Res. 2022; 50:D439–D444. PubMed PMC

Raček T., Schindler O., Toušek D., Horský V., Berka K., Koča J., Svobodová R.. Atomic Charge Calculator II: web-based tool for the calculation of partial atomic charges. Nucleic Acids Res. 2020; 48:W591–W596. PubMed PMC

Kangas E., Tidor B.. Electrostatic complementarity at ligand binding sites: application to chorismate mutase. J. Phys. Chem. B. 2001; 105:880–888.

Gitlin I., Carbeck J.D., Whitesides G.M.. Why are proteins charged? Networks of charge–charge interactions in proteins measured by charge ladders and capillary electrophoresis. Angew. Chem. 2006; 45:3022–3060. PubMed

Park H., Lee J., Lee S.. Critical assessment of the automated AutoDock as a new docking tool for virtual screening. Proteins. 2006; 65:549–554. PubMed

Rappé A.K., Goddard III W.A.. Charge equilibration for molecular dynamics simulations. J. Phys. Chem. 1991; 95:3358–3363.

Nazarian D., Camp J.S., Sholl D.S.. A comprehensive set of high-quality point charges for simulations of metal–organic frameworks. Chem. Mater. 2016; 28:785–793.

Boda D., Gillespie D., Nonner W., Henderson D., Eisenberg B.. Computing induced charges in inhomogeneous dielectric media: application in a Monte Carlo simulation of complex ionic systems. Phys. Rev. E. 2004; 69:046702. PubMed

Shankar R. Principles of Quantum Mechanics. 2012; NY: Springer.

Reed A.E., Weinhold F.. Natural bond orbital analysis of near-Hartree–Fock water dimer. J. Chem. Phys. 1983; 78:4066–4073.

Reed A.E., Weinstock R.B., Weinhold F.. Natural population analysis. J. Chem. Phys. 1985; 83:735–746.

Schindler O., Raček T., Maršavelski A., Koča J., Berka K., Svobodová R.. Optimized SQE atomic charges for peptides accessible via a web application. J. Cheminform. 2021; 13:45. PubMed PMC

Søndergaard C.R., Olsson M.H., Rostkowski M., Jensen J.H.. Improved treatment of ligands and coupling effects in empirical calculation and rationalization of pKa values. J. Chem. Theory Comput. 2011; 7:2284–2295. PubMed

Olsson M.H., Søndergaard C.R., Rostkowski M., Jensen J.H.. PROPKA3: consistent treatment of internal and surface residues in empirical pKa predictions. J. Chem. Theory Comput. 2011; 7:525–537. PubMed

Sehnal D., Bittrich S., Deshpande M., Svobodová R., Berka K., Bazgier V., Velankar S., Burley S.K., Koča J., Rose A.S.. Mol* Viewer: modern web app for 3D visualization and analysis of large biomolecular structures. Nucleic Acids Res. 2021; 49:W431–W437. PubMed PMC

Burley S.K., Bhikadiya C., Bi C., Bittrich S., Chen L., Crichlow G.V., Christie C.H., Dalenberg K., Di Costanzo L., Duarte J.M.et al. .. RCSB Protein Data Bank: powerful new tools for exploring 3D structures of biological macromolecules for basic and applied research and education in fundamental biology, biomedicine, biotechnology, bioengineering and energy sciences. Nucleic Acids Res. 2021; 49:D437–D451. PubMed PMC

Mortier W.J., Ghosh S.K., Shankar S.. Electronegativity equalization method for the calculation of atomic charges in molecules. J. Am. Chem. Soc. 1986; 108:4315–4320.

Nistor R.A., Polihronov J.G., Müser M.H., Mosey N.J.. A generalization of the charge equilibration method for nonmetallic materials. J. Chem. Phys. 2006; 125:094108. PubMed

Dolinsky T.J., Nielsen J.E., McCammon J.A., Baker N.A.. PDB2PQR: an automated pipeline for the setup of Poisson–Boltzmann electrostatics calculations. Nucleic Acids Res. 2004; 32:W665–W667. PubMed PMC

Ionescu C.-M., Sehnal D., Falginella F.L., Pant P., Pravda L., Bouchal T., Svobodová Vařeková R., Geidl S., Koča J.. AtomicChargeCalculator: interactive web-based calculation of atomic charges in large biomolecular complexes and drug-like molecules. J. Cheminform. 2015; 7:50. PubMed PMC

Leslie E.M., Deeley R.G., Cole S.P.. Multidrug resistance proteins: role of P-glycoprotein, MRP1, MRP2, and BCRP (ABCG2) in tissue defense. Toxicol. Appl. Pharmacol. 2005; 204:216–237. PubMed

Ward A.B., Szewczyk P., Grimard V., Lee C.-W., Martinez L., Doshi R., Caya A., Villaluz M., Pardon E., Cregger C.et al. .. Structures of P-glycoprotein reveal its conformational flexibility and an epitope on the nucleotide-binding domain. Proc. Natl. Acad. Sci. U.S.A. 2013; 110:13386–13391. PubMed PMC

Heda R., Toro F., Tombazzi C.R.. Physiology, pepsin. StatPearls. 2022; Treasure Island, FL: StatPearls Publishing. PubMed

Stanforth K.J., Wilcox M.D., Chater P.I., Brownlee I.A., Zakhour M.I., Banecki K., Pearson J.P.. Pepsin properties, structure, and its accurate measurement: a narrative review. Ann. Esophagus. 2022; 5:31.

Tanaka T., Yada R.Y.. N-terminal portion acts as an initiator of the inactivation of pepsin at neutral pH. Protein Eng. Des. Sel. 2001; 14:669–674. PubMed

Grahame D.A., Dupuis J.H., Bryksa B.C., Tanaka T., Yada R.Y.. Improving the alkaline stability of pepsin through rational protein design using renin, an alkaline-stable aspartic protease, as a structural and functional reference. Enzyme Microb. Technol. 2021; 150:109871. PubMed

Ung K.L., Winkler M., Schulz L., Kolb M., Janacek D.P., Dedic E., Stokes D.L., Hammes U.Z., Pedersen B.P.. Structures and mechanism of the plant PIN-FORMED auxin transporter. Nature. 2022; 609:605–610. PubMed PMC

Yang Z., Xia J., Hong J., Zhang C., Wei H., Ying W., Sun C., Sun L., Mao Y., Gao Y.et al. .. Structural insights into auxin recognition and efflux by Arabidopsis PIN1. Nature. 2022; 609:611–615. PubMed PMC

Su N., Zhu A., Tao X., Ding Z.J., Chang S., Ye F., Zhang Y., Zhao C., Chen Q., Wang J.et al. .. Structures and mechanisms of the Arabidopsis auxin transporter PIN3. Nature. 2022; 609:616–621. PubMed

Mapping the membrane orientation of auxin homeostasis regulators PIN5 and PIN8 in Arabidopsis thaliana root cells reveals their divergent topology