1. ABOUT THE DATASET ------------ Title: Dataset for an ab initio study of the selectivity of dopamine and other ligands for various dopamine-related enzymes. Creator(s): Mauricio Cafiero [1] (ORCID: 0000-0002-4895-1783), Joshua Harle [2] Organisation(s): 1. University of Reading. 2. University of Wolverhampton Rights-holder(s): University of Reading, Joshua Harle (Student). Publication Year: 2023 Description: Interaction energy calculations between the ligands dopamine, L-DOPA, paracetamol, NAPQI, 3-hydroxyparacetamol, phenylalanine, tyrosine, DOPAL, DOPAC, 3-methoxytyramine and homovanilin with the active sites of the enzymes phenylalanine hydroxylase, tyrosine hydroxylase, DOPA decarboxylase, tyrosinase, COMT, MAO, ALDH, and SULT. These calculations performed with M062X/6-31G//M062X/6-311+G*. Also included are desolvation energy calculations for all ligands named here using M062X/cc-pvdz, as well as benchmark MP2 calculations of dopamine and paracetamol with the SULT active site. All calculations performed using Gaussian 16. Complete and raw data for manuscript "Ab initio study of the selectivity of Dopamine, L-DOPA, Paracetamol and its metabolite NAPQI for various enzymes associated with biosynthesis and metabolism of Dopamine," by Harle, Slater and Cafiero. Cite as: Cafiero, Mauricio and Harle, Joshua (2023): Dataset for an ab initio study of the selectivity of dopamine and other ligands for various dopamine-related enzymes. University of Reading. Dataset. https://doi.org/10.17864/1947.000459 Related publication: J. Harle, C. Slater, and M. Cafiero, "Ab initio study of the selectivity of Dopamine, L-DOPA, Paracetamol and its metabolite NAPQI for various enzymes associated with biosynthesis and metabolism of Dopamine." Submitted, ACS Neuroscience. Contact: m.cafiero@reading.ac.uk 2. TERMS OF USE ------------ Copyright 2023 University of Reading, Joshua Harle. This dataset is licensed under a Creative Commons Attribution 4.0 International Licence: https://creativecommons.org/licenses/by/4.0/. 3. PROJECT AND FUNDING INFORMATION ------------ Title: A novel dynamic Density Functional Theory method for analysing multi-scale ligand/protein interactions Dates: Sept. 2022- August 2023 Funding organisation: The Royal Society of Chemistry Grant no.: Research Enablement Grant (E21-9051333819) 4. CONTENTS ------------ File listing Paracetamol-Tables-Cafiero-Feb2023.xlsx This file contains raw data for the calculation of: 1. Electronic interaction energies between a set of ligands and the active sites of 8 enzymes calculated using the method: M062X/6-31G//M062X/6-311+g*, 2. Benchmark interaction energies between paracetamol and dopamine and the active site of the SULT enzyme using the method: M062X/6-31G//MP2/6-311+g*, 3. Desolvation energies of all of the ligands studied, and 4. electronic binding energies between the ligands and the active sites made by combining (1) and (2) with (3). All calculations performed using the Gaussian 16 software (www.Gaussian.com). Tab Contents Equations Equations used in excel formulae NAPQI-PCM+desolvation DFT Interaction energy calculations for NAPQI and Paracetamol (PCM) with all 8 enzymes studied (PheOH, TyrOH, Dopa Decarboxylase, COMT, MAO, ALDH, tyrosinase and SULT). Also Desolvation energy calculations for all ligands, and plot of dipoles versus desolvation energy. Summary data tables here as well. Dopamine DFT Interaction energy calculations for Dopamine with all 8 enzymes studied (PheOH, TyrOH, Dopa Decarboxylase, COMT, MAO, ALDH, tyrosinase and SULT). L-DOPA DFT Interaction energy calculations for L-DOPA with all 8 enzymes studied (PheOH, TyrOH, Dopa Decarboxylase, COMT, MAO, ALDH, tyrosinase and SULT). Substrates DFT Interaction energy calculations for natural substrates for the enzymes studied (PheOH, TyrOH, Dopa Decarboxylase, COMT, MAO, ALDH, tyrosinase and SULT). MP2 Interaction energies for PCM and dopamine with the SULT active site calculated with MP2. Acronyms Variables PCM Paracetamol HV Homovanilin PheOH Phenylalanine Hydroxylase TyrOH Tyrosine Hydroxylase DDC DOPA decarboxylase COMT Catechol o-methyltransferase MAO Monoamine oxidase ALDH aldehyde dehydrogenase AA amino acid IE interaction energy 3MT 3-methytyramine 3HP 3-hydroxyparacetamol 5. METHODS ----------- The methods below are adapted from the manuscript named above which has been submitted to review to a journal. Desolvation energies and free energies for paracetamol, NAPQI, dopamine, L-DOPA and the other intermediate molecules studied here (phenylalanine, tyrosine, DOPAL, DOPAC, homovanilin, 3-methoxytyramine, and 3-hydroxyparacetamol) were calculated using M062X/cc-pvtz. Each of the ligand molecules was then surrounded by 11 water molecules and the structures of the solvated complexes were optimized to global minima, as evidenced by no imaginary vibrational frequencies. Each of the ligands was then optimized to a global minimum without the surrounding water molecules, as was a cluster of 11 water molecules. Energies and free energies were calculated for all molecules at 298.15 K according to the equations given in the xlsx file indicated above. The formula for calculating the total electronic energy of binding used here is also given in the xlsx file. Each of the ligands was then studied in up to eight enzyme active sites relevant to dopamine synthesis and metabolism. Paracetamol, NAPQI, dopamine, and L-DOPA were studied in all eight active sites, while the rest of the ligands were studied only in those enzymes for which they are a natural substrate. The isolation and preparation of active sites for aldehyde dehydrogenase (ALDH), phenylalanine hydroxylase (PheOH), tyrosine hydroxylase (TyrOH), sulfotransferase (SULT1A3), and catechol-o-methyltransferase (COMT) has been described in our previous published work (D. J. Bigler, L. W. Peterson and M. Cafiero, Comput Theor Chem, 2015, 1051, 79–92; A. K. Hatstat, M. Morris, L. W. Peterson and M. Cafiero, Comput Theor Chem, 2016, 1078, 146–162; R. Evans, L. Peterson and M. Cafiero, Comput Theor Chem, 2018, 1140, 145–151; M. C. Perchik, L. W. Peterson and M. Cafiero, Comput Theor Chem, 2019, 1153, 19–24; C. A. Magee, L. W. Peterson, M. Cafiero and E. F. Selner, Comput Theor Chem, 2020, 1185, 112868). For the remaining three enzymes, crystal structures of each with a bound ligand were downloaded from the Protein Data Bank.The active sites were identified as all amino acid residues with any atom within 3 angstroms of any atom of the ligand bound in the crystal structure. For monoamine oxidase (MAO) this resulted in an active site consisting of trp618, pro603, tyr934, tyr897, tyr825, tyr559, phe842, phe602, phe667, leu670, pro601, leu663, ile698, cys671, gln705, ile815, ile697, and the cofactor FAD. For tyrosinase22, the resulting active site included ala221, asn205, gly216, his42, his60, his69, his204, his208, his231, met215, phe197, phe227, val217, and val218. For dopa-decarboxylase (DDC)23 the active site included phe579, phe309, phe80, ile, trp, lys, his192, his302, pro, thr82, thr246, tyr, and the cofactor pyridoxal phosphate (PLP). In all cases, amino acid residues were capped with -H or -OH to maintain the charge found in the full protein structure. All ligands were optimized in each active site using M062X/6-31G24 using implicit solvent (water) via the polarizable continuum model. During the optimization, all nuclei in the ligands, all nuclei in the amino acid residue side-chains, and all protons were relaxed. The counterpoise-corrected pairwise interaction energies between each optimized ligand and the i-th active site amino acid residue were calculated using M062X/6-311+G* according to the equation given in the indicated xlsx file, where the energies of the ligand and amino acid residue include all of the basis functions and DFT grid points of the ghost atoms from the other molecule. The pairwise interaction energies were summed to find the total electronic interaction energies per ligand in each active site. The above interaction energy calculations were performed with second order perturbation theory in addition to DFT for paracetamol and dopamine in the SULT active site in order to benchmark the DFT calculations.