IRMPD spectroscopy and quantum-chemical simulations of the reaction products of cisplatin with the dipeptide CysGly

Corinti, Davide; Paciotti, Roberto; Coletti, Cecilia; Re, Nazzareno; Chiavarino, Barbara; Frison, Gilles; Crestoni, Maria Elisa; Fornarini, Simonetta

doi:10.1016/j.jinorgbio.2023.112342

Cited by 3 publications

(2 citation statements)

References 75 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The optimized geometries resulting from either MTD or MD studies were then analyzed by using the fragment molecular orbitals (FMO) methodology and adopting the three-body approach (FMO3) [ 32 ]. Notably, although the FMO method is widely applied for the investigation of interactions involving large biological systems as proteins structure [ 33 , 34 ], protein–protein interaction [ 35 , 36 ], protein–DNA interaction [ 37 ] and ligand-receptor complexes [ 38 , 39 ], it can be used also to study small metal complexes as previously done [ 40 ]. Here, the FMO method can be profitably used to monitor the ligand exchange reactions in terms of pair interaction energies (PIEs) because the composition of the fragments is not altered by the breaking/formation of coordinate bonds during reaction.…”

Section: Methodsmentioning

confidence: 99%

A computational insight on the aromatic amino acids conjugation with [Cp*Rh(H2O)3]2+ by using the meta-dynamics/FMO3 approach

Paciotti,

Marrone

2023

J Mol Model

Self Cite

View full text Add to dashboard Cite

Context Rh(III) complexes demonstrated to exert promising pharmacological effects with potential applications as anti-cancer, anti-bacterial, and antimicrobial agents. One important Rh(III)-ligand is the pentamethylcyclopentadienyl (Cp*) group forming in water the [Cp*Rh(H2O)3]2+ complex. Among of its attractive chemical properties is the ability to react specifically with Tyr amino acid side chain of G-protein–coupled receptor (GPCR) peptides by means of highly chemoselective bioconjugation reaction, at room temperature and at pH 5–6. In this computational work, in order to deepen the mechanism of this chemoselective conjugation, we study the ligand exchange reaction between [Cp*Rh(H2O)3]2+ and three small molecules, namely p-cresol, 3-methylimidazole, and toluene, selected as mimetic of aromatic side chains of tyrosine (Tyr), tryptophan (Trp) and phenylalanine (Phe), respectively. Our outcomes suggest that the high selectivity for Tyr side chain might be related to OH group able to affect both thermodynamic and kinetic of ligand exchange reaction, due to its ability to act as both H bond acceptor and donor. These mechanistic aspects can be used to design new metal drugs containing the [Cp*Rh]2+ scaffold targeting specifically Tyr residues involved in biological/pathological processes such as phosphorylation by means of Tyr-kinase enzyme and protein–protein interactions. Methods The geometry of three encounter complexes and product adducts were optimized at the B3LYP//CPCM/ωB97X-D level of theory, adopting the 6-311+G(d,p) basis set for all non-metal atoms and the LANL2DZ pseudopotential for the Rh atom. Meta-dynamics RMSD (MTD(RMSD)) calculations at GFN2-xTB level of theory were performed in NVT conditions at 298.15 K to investigate the bioconjugation reactions (simulation time: 100 ps; integration step 2.0; implicit solvent model: GBSA). The MTD(RMSD) simulation was performed in two replicates for each encounter complex. Final representative subsets of 100 structures for each run were gained with a sampling rate of 1 ps and analyzed by performing single point calculations using the FMO3 method at RI-MP2/6-311G//PCM[1] level of theory, adopting the MCP-TZP core potential for Rh atom.

show abstract

Section: Methodsmentioning

confidence: 99%

A computational insight on the aromatic amino acids conjugation with [Cp*Rh(H2O)3]2+ by using the meta-dynamics/FMO3 approach

Paciotti,

Marrone

2023

J Mol Model

Self Cite

View full text Add to dashboard Cite

show abstract

“…The FMO2 approach with the implicit solvation method has been widely applied to study biological systems as protein-protein interactions [ 6 , 7 ], protein-DNA interactions [ 8 ], protein structures and stability [ 9 ], ligand-receptor interactions [ 10 ] and small metal complexes [ 11 ]. Systems that can profitably be investigated by the application of the ab initio FMO method are receptors, typically bio-macromolecules, that natively bind metals and/or interact with metallic compounds.…”

Section: Introductionmentioning

confidence: 99%

Improving the accuracy of the FMO binding affinity prediction of ligand-receptor complexes containing metals

Paciotti,

Marrone,

Coletti

et al. 2023

J Comput Aided Mol Des

View full text Add to dashboard Cite

Polarization and charge transfer strongly characterize the ligand-receptor interaction when metal atoms are present, as for the Au(I)-biscarbene/DNA G-quadruplex complexes. In a previous work (J Comput Aided Mol Des2022, 36, 851–866) we used the ab initio FMO2 method at the RI-MP2/6-31G* level of theory with the PCM [1] solvation approach to calculate the binding energy (ΔEFMO) of two Au(I)-biscarbene derivatives, [Au(9-methylcaffein-8-ylidene)2]+ and [Au(1,3-dimethylbenzimidazole-2-ylidene)2]+, able to interact with DNA G-quadruplex motif. We found that ΔEFMO and ligand-receptor pair interaction energies (EINT) show very large negative values making the direct comparison with experimental data difficult and related this issue to the overestimation of the embedded charge transfer energy between fragments containing metal atoms. In this work, to improve the accuracy of the FMO method for predicting the binding affinity of metal-based ligands interacting with DNA G-quadruplex (Gq), we assess the effect of the following computational features: (i) the electron correlation, considering the Hartree–Fock (HF) and a post-HF method, namely RI-MP2; (ii) the two (FMO2) and three-body (FMO3) approaches; (iii) the basis set size (polarization functions and double-ζ vs. triple-ζ) and (iv) the embedding electrostatic potential (ESP). Moreover, the partial screening method was systematically adopted to simulate the solvent screening effect for each calculation. We found that the use of the ESP computed using the screened point charges for all atoms (ESP-SPTC) has a critical impact on the accuracy of both ΔEFMO and EINT, eliminating the overestimation of charge transfer energy and leading to energy values with magnitude comparable with typical experimental binding energies. With this computational approach, EINT values describe the binding efficiency of metal-based binders to DNA Gq more accurately than ΔEFMO. Therefore, to study the binding process of metal containing systems with the FMO method, the adoption of partial screening solvent method combined with ESP-SPCT should be considered. This computational protocol is suggested for FMO calculations on biological systems containing metals, especially when the adoption of the default ESP treatment leads to questionable results.

show abstract

Combining the Fragment Molecular Orbital and GRID Approaches for the Prediction of Ligand–Metalloenzyme Binding Affinity: The Case Study of hCA II Inhibitors

Paciotti,

Re,

Storchi

2024

Molecules

View full text Add to dashboard Cite

Polarization and charge-transfer interactions play an important role in ligand–receptor complexes containing metals, and only quantum mechanics methods can adequately describe their contribution to the binding energy. In this work, we selected a set of benzenesulfonamide ligands of human Carbonic Anhydrase II (hCA II)—an important druggable target containing a Zn2+ ion in the active site—as a case study to predict the binding free energy in metalloprotein–ligand complexes and designed specialized computational methods that combine the ab initio fragment molecular orbital (FMO) method and GRID approach. To reproduce the experimental binding free energy in these systems, we adopted a machine-learning approach, here named formula generator (FG), considering different FMO energy terms, the hydrophobic interaction energy (computed by GRID) and logP. The main advantage of the FG approach is that it can find nonlinear relations between the energy terms used to predict the binding free energy, explicitly showing their mathematical relation. This work showed the effectiveness of the FG approach, and therefore, it might represent an important tool for the development of new scoring functions. Indeed, our scoring function showed a high correlation with the experimental binding free energy (R2 = 0.76–0.95, RMSE = 0.34–0.18), revealing a nonlinear relation between energy terms and highlighting the relevant role played by hydrophobic contacts. These results, along with the FMO characterization of ligand–receptor interactions, represent important information to support the design of new and potent hCA II inhibitors.

show abstract

IRMPD spectroscopy and quantum-chemical simulations of the reaction products of cisplatin with the dipeptide CysGly

Cited by 3 publications

References 75 publications

A computational insight on the aromatic amino acids conjugation with [Cp*Rh(H2O)3]2+ by using the meta-dynamics/FMO3 approach

A computational insight on the aromatic amino acids conjugation with [Cp*Rh(H2O)3]2+ by using the meta-dynamics/FMO3 approach

Improving the accuracy of the FMO binding affinity prediction of ligand-receptor complexes containing metals

Combining the Fragment Molecular Orbital and GRID Approaches for the Prediction of Ligand–Metalloenzyme Binding Affinity: The Case Study of hCA II Inhibitors

Contact Info

Product

Resources

About