Modeling SARS-CoV-2 spike/ACE2 protein-protein interactions for predicting the binding affinity of new spike variants for ACE2, and novel ACE2 structurally related human protein targets, for COVID-19 handling in the 3PM context.

"in order to obtain a pose of the 3d protein complex of sars-cov-2 spike rbd mutants interacting with ace2 the built 3d comparative models of the mutants were superimposed to the 3d protein complex consisting of the wuhan sars-cov-2 spike rbd interacting with ace2 available under the 6m0j pdb protein data bank (pdb) entry.; the crystallized structures of the proteins sampled by pgenthreader and i-tasser analysis were structurally aligned with the 3d coordinates of ace2 available under the pdb_id 6m0j pdb.; the 3d coordinates of the wuhan sars-cov-2 spike rbd crystallized in complex with the human ace2 receptor available under the pdb_id 6m0j pdb were used to estimate the binding affinity of the sars-cov-2 spike rbd for the human ace2 (i e from the reference sequence np_001358344 1) by using the foldx analysecomplex assay [ ].; a the sars-cov-2 spike rbd crystallized structure (6m0j pdb) is reported in white cartoon representation.; clinicians and researchers can directly upload through the provided link both the sequenced spike rbd and ace2 amino acid sequences for calculating the sars-cov-2 spike rbd/ace2 interaction energies to be compared with interaction energies obtained at the protein-protein interface within the crystallized protein complex (6m0j pdb) consisting of the hcov 19wuhan wiv04 2019 rbd (yp_009724390 1) and the ace2 reference protein (np_001358344 1) and/or the other interaction energies data available from this manuscript for estimating a possible higher transmissibility or virulence of future detected variants depending on an increased predicted sars-cov-2 spike rbd/ace2 binding affinity ace2 sequence was used for screening the pdb searching for ace2 structurally related proteins that might work as host-cell entry sites for sars-cov-2.; interaction energies are also reported in kj/mol (1 kcal = 4 184 kj) items and energy terms ace2 (6m0j pdb) ace (6h5w pdb) nln (1i1i pdb) thop1 (1s4b pdb) group 1 (chain) a (ace2) a (ace1) p (nln) p (thop) group 2 (chain) e (rbd_6m0j) e (rbd_6m0j) e (rbd_6m0j) e (rbd_6m0j) interaction energy (kj/mol) - 85 85 - 31 02 - 99 29 - 92 09 interaction energy (kcal/mol) - 20 51 - 7 41 - 23 72 - 22 00 intraclashes group 1 22 28 22 95 21 50 22 95 intraclashes group 2 5 49 6 63 13 07 9 70 backbone h-bond (kcal/mol) - 3 64 - 0 16 - 13 08 - 7 86 sidechain h-bond (kcal/mol) - 12 12 - 9 76 - 19 3 - 9 39 van der waals (kcal/mol) - 15 89 - 7 81 - 55 11 - 48 08 electrostatics (kcal/mol) - 2 41 - 2 65 - 1 62 - 3 31 solvation polar (kcal/mol) 22 14 12 62 84 22 76 28 solvation hydrophobic (kcal/mol) - 20 02 - 9 90 - 68 74 - 60 04 van der waals clashes (kcal/mol) 0 41 0 06 6 96 2 91 entropy side chain (kcal/mol) 9 53 9 02 18 80 18 02 entropy main chain (kcal/mol) 1 57 1 33 21 16 8 86 torsional clash (kcal/mol) 0 083 0 055 3 68 0 94 backbone clash (kcal/mol) 2 45 0 79 17 26 14 11 helix dipole (kcal/mol) - 0 06 - 0 02 - 0 00 0 14 disulfide (kcal/mol) 1 78e - 15 3 55e - 15 0 0 electrostatic kon (kcal/mol) - 0 18 - 0 20 - 0 67 - 0 47 energy ionization (kcal/mol) 0 07 - 2 84e - 16 7 06e - 03 1 60e - 16 entropy complex (kcal/mol) 2 38 2 38 2 38 2 38 number of residues791 780 859 848 gtex database was screened for estimating the expression levels of ace2 ace thop1 and nln together with other sars-cov-2 host-cell entry factors in all the tissues available on gtex.; previously [ ] we have determined the interaction energies between the sars-cov-2 spike rbd and the human ace2 receptor available under the pdb_id 6vw1 pdb [ ].; the chimeric rbd from 6vw1 pdb showed 22 missense mutations and the deletion of three residues at the rbd with respect to the amino acid sequence of sars-cov-2 spike rbd according to the wuhan reference sequence available under the refseq accession number yp_009724390 1.; less than one year ago the coordinates of the sars-cov-2 spike rbd (according to yp_009724390 1) crystallized in complex with the human ace2 receptor were made available under the pdb_id 6mo0j pdb [ ]."

"Declarations Ethics approvalNA Consent to participateNA Consent for publicationNA Conflict of interestThe authors declare no competing interests. Conflict of interest The authors declare no competing interests."

"Funding The Italian Association for Mitochondrial Research (www.mitoairm.it) provided part of the computational resources used for the presented analyses."