scholarly journals Binding motifs of cisplatin interaction with simple biomolecules and aminoacid targets probed by IR ion spectroscopy

2020 ◽  
Vol 92 (1) ◽  
pp. 3-13 ◽  
Author(s):  
Davide Corinti ◽  
Roberto Paciotti ◽  
Nazzareno Re ◽  
Cecilia Coletti ◽  
Barbara Chiavarino ◽  
...  
Keyword(s):  
Biological Activity ◽  
Amino Acid ◽  
Gas Phase ◽  
Quantum Chemical ◽  
Ligand Substitution ◽  
Side Chain ◽  
Binding Motifs ◽  
Distinctive Features ◽  
Ion Spectroscopy ◽  
Vibrational Action

AbstractThe primary intermediates resulting from the interaction of cisplatin, cis-(PtCl2(NH3)2], most widespread antitumor drug, with biomolecular targets are characterized. Electrospray ionization is used to deliver ions formed in solution into the gas phase where they are structurally interrogated by vibrational “action” spectroscopy in conjunction with quantum chemical calculations. The aquation products, cis-[PtX(NH3)2(H2O)]+ (X = Cl, OH), lying along the path responsible for biological activity, are shown to display distinctive features responding to ligation pattern and optimized geometry. The IR spectra of trans-[PtX(NH3)2(H2O)]+ are different, testifying that cis and trans complexes are stable, non interconverting species both in solution and in the gas phase. Ligand substitution by simple nucleophiles (L = pyridine, 4(5)-methylimidazole, thioanisole, trimethylphosphate, acetamide, dimethylacetamide, urea and thiourea) yields cis-[PtCl(NH3)2(L)]+ complexes displaying remarkable regioselectivity whenever L presents multiple candidate platination sites. The incipient formation of cisplatin-derived complexes with the recognized biological amino acid targets L-histidine (His) and L-methionine (Met) has been investigated revealing the primary platination event to be mainly directed at the Nπ atom of the imidazole side chain of His and to the thiomethyl sulfur of Met. The isomer and conformer population of the ensuing cis-[PtCl(NH3)2(Met/His)]+ complexes, sampled in the gas phase, can be ascertained by photofragmentation kinetics on isomer/conformer specific resonances.

scholarly journals Experimental and theoretical investigations of infrared multiple photon dissociation spectra of lysine complexes with Zn2+ and Cd2+

2018 ◽  
Vol 25 (1) ◽  
pp. 97-111 ◽  
Author(s):  
Cameron J Owen ◽  
Georgia C Boles ◽  
Giel Berden ◽  
Jos Oomens ◽  
PB Armentrout
Keyword(s):  
Amino Acid ◽  
Gas Phase ◽  
Single Point ◽  
Basis Sets ◽  
Side Chain ◽  
Amine Group ◽  
Linear Absorption ◽  
Action Spectra ◽  
Phase Structures ◽  
Infrared Multiple Photon Dissociation

The gas-phase structures of zinc and cadmium complexes of lysine (Lys) are investigated via a combination of infrared multiple photon dissociation action spectroscopy and ab initio quantum chemical calculations. In order to unambiguously identify the experimentally observed species, [Zn(Lys−H)]+ and CdCl+(Lys), the action spectra were compared to linear absorption spectra calculated at the B3LYP level of theory, using 6-311+G(d,p) and def2-TVZP basis sets for the zinc and cadmium systems, respectively. Single point energies were also calculated at the B3LYP, B3P86, MP2, and B3LYP-GD3BJ (accounting for empirical dispersion) levels of theory using larger basis sets. Identification of the experimentally formed isomers is possible through good agreement between infrared multiple photon dissociation action spectra and the theoretically predicted spectra. The [Zn(Lys−H)]+ complex adopts a tridentate orientation involving the amino acid backbone amine and deprotonated carboxylic acid groups as well as the side-chain amine group, [Nα,CO−,Nɛ]. The CdCl+(Lys) complex similarly adopts a tridentate chelation involving the amino acid backbone amine and carbonyl groups, as well as the side-chain amine group, [Nα,CO,Nɛ]. In both cases, the identified complexes are the lowest energy gas-phase structures at all levels of theory.

scholarly journals Structure of isolated tyrosyl-glycyl-glycine tripeptide. A comparative conformational study with peptides containing an aromatic ring

2010 ◽  
Vol 8 (3) ◽  
pp. 566-575 ◽  
Author(s):  
Exequiel Barrera Guisasola ◽  
Marcelo Masman ◽  
Ricardo Enriz ◽  
Ana Rodríguez
Keyword(s):  
Gas Phase ◽  
Quantum Chemical ◽  
Computational Analysis ◽  
Energy Surface ◽  
Side Chain ◽  
Small Peptides ◽  
Peptide Backbone ◽  
X Ray ◽  
Backbone Conformation ◽  
Glycyl Glycine

AbstractThe potential energy surface (PES) of tyrosyl-glycyl-glycine (YGG) tripeptide in solution was explored using EDMC (Electrostatically Driven Monte Carlo) and in the gas-phase by means of ab initio quantum chemical calculations. The theoretical computational analysis revealed that this tripeptide possesses a significant molecular flexibility. A C7 backbone conformation was the most energetically preferred for the central Gly residue, using both methodologies. Some new stable conformers that have not been previously reported were identified in the gas phase as well. This study points out the interplay of backbone and side-chain contributions in determining the relative stabilities of energy minima. In addition, the peptide backbone of YGG was compared with other small peptides containing aromatic side-chains (Phe-Gly-Gly and Trp-Gly-Gly). The comparison with experimental X-ray results was also satisfactory.

scholarly journals Side-chain effects on the structures of protonated amino acid dimers: A gas-phase infrared spectroscopy study

2018 ◽  
Vol 429 ◽  
pp. 115-120 ◽  
Author(s):  
Jongcheol Seo ◽  
Waldemar Hoffmann ◽  
Sebastian Malerz ◽  
Stephan Warnke ◽  
Michael T. Bowers ◽  
...  
Keyword(s):  
Infrared Spectroscopy ◽  
Amino Acid ◽  
Gas Phase ◽  
Side Chain ◽  
Spectroscopy Study ◽  
Protonated Amino Acid

scholarly journals The semisynthesis of fragments corresponding to residues 66-104 of horse heart cytochrome c

1979 ◽  
Vol 179 (1) ◽  
pp. 169-182 ◽  
Author(s):  
C J Wallace ◽  
R E Offord
Keyword(s):  
Biological Activity ◽  
Amino Acid ◽  
Cytochrome C ◽  
Amino Acid Sequences ◽  
Side Chain ◽  
Horse Heart Cytochrome ◽  
Natural Sequence ◽  
C Terminus ◽  
N Terminus ◽  
Horse Heart Cytochrome C

We describe the N epsilon-acetimidylation of horse heart cytochrome c with retention of biological activity, the cleavage of the modified protein by CNBr, the separation of the fragments, and their further side-chain protection. We describe the manipulation of the amino acid sequences of the fragments by stepwise semisynthetic methods. We have prepared fragments corresponding to residues 66-78 and 66-79 of the protein, as well as the [Asp66] analogue of fragment 66-79. We have prepared the natural sequence and the [o-fluoro-Phe82] analogue of the fragment corresponding to residues 81-104 of the protein, and the [N epsilon-trifluoroacetyl-Lys79], the [N epsilon-dinitrophenyl-Lys79] and the [S-acetamidomethyl-Cys79] analogues of fragment 79-104, and the [N epsilon-Cbz-Lys81] analogue of fragment 80-104. We have coupled back the fragments of natural sequence to form a semisynthetic fragment corresponding to residues 66-104 of the protein. Modified fragments were also coupled to give analogues of the 66-104-residue sequence. In every case the homoserine residue representing methionine-80 was removed from the C-terminus of the 66-80-residue fragment and replaced by methionine on the N-terminus of the 81-104 residue fragment during the preparation of the fragments for coupling. The semisynthetic fragments are ready for specific deprotection and further coupling. We have coupled one such fragment to the (1-65)-peptide to produce semisynthetic [Hse65]cytochrome c. The product has satisfactory characteristics on chemical analysis, and on assay of its biological activity.

Prediction of Alkanolamine pKa Values by Combined Molecular Dynamics Free Energy Simulations and ab initio Calculations

2019 ◽  
Author(s):  
Javad Noroozi ◽  
William Smith
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Ab Initio Calculations ◽  
Gas Phase ◽  
Quantum Chemical ◽  
Phase Reaction ◽  
Pka Values ◽  
Gas Phase Reaction ◽  
Reaction Free Energy ◽  
Energy Simulations

We use molecular dynamics free energy simulations in conjunction with quantum chemical calculations of gas phase reaction free energy to predict alkanolamines pka values. <br>

Polypeptides Folding: Rules for the Calculation of the Backbone Dihedral Angles φ starting from the Amino Acid Sequence

2020 ◽  
Author(s):  
Michele Larocca
Keyword(s):  
Amino Acid ◽  
Amino Acid Sequence ◽  
Theoretical Approach ◽  
Polypeptide Chain ◽  
Hydrophobic Effect ◽  
Side Chain ◽  
Dihedral Angles ◽  
Mechanical Forces ◽  
Specific Chemical

<p>Protein folding is strictly related to the determination of the backbone dihedral angles and depends on the information contained in the amino acid sequence as well as on the hydrophobic effect. To date, the type of information embedded in the amino acid sequence has not yet been revealed. The present study deals with these problematics and aims to furnish a possible explanation of the information contained in the amino acid sequence, showing and reporting rules to calculate the backbone dihedral angles φ. The study is based on the development of mechanical forces once specific chemical interactions are established among the side chain of the residues in a polypeptide chain. It aims to furnish a theoretical approach to predict backbone dihedral angles which, in the future, may be applied to computational developments focused on the prediction of polypeptide structures.</p>

Synthesis of New α-Amino Phosphonates Containing 3-Amino-4(3H) Quinazolinone Moiety as Anticancer and Antimicrobial Agents: DFT, NBO, and Vibrational Studies

2018 ◽  
Vol 15 (2) ◽  
pp. 286-296 ◽  
Author(s):  
Mohamed K. Awad ◽  
Mahmoud F. Abdel-Aal ◽  
Faten M. Atlam ◽  
Hend A. Hekal
Keyword(s):  
Biological Activity ◽  
Cell Line ◽  
Quantum Chemical ◽  
Density Functional ◽  
Carcinoma Cell ◽  
Liver Carcinoma ◽  
Anticancer Activities ◽  
Functional Theory ◽  
Ft Ir ◽  
Good Agreement

Aim and Objective: Synthesis of new .-aminophosphonates containing quinazoline moiety through Kabachnik-Fields reaction in the presence of copper triflate catalyst [32], followed by studying their antimicrobial activities and in vitro anticancer activities against liver carcinoma cell line (HepG2) with the hope that new anticancer agents could be developed. Also, the quantum chemical calculations are performed using density functional theory (DFT) to study the effect of the changes of molecular and electronic structures on the biological activity of the investigated compounds. Materials and Method: The structures of the synthesized compounds are confirmed by FT-IR, 1H NMR, 13C NMR, 31P NMR and MS spectral data. The synthesized compounds show significant antimicrobial and also remarkable cytotoxicity anticancer activities against liver carcinoma cell line (HepG2). Density functional theory (DFT) was performed to study the effect of the molecular and electronic structure changes on the biological activity. Results: It was found that the electronic structure of the substituents affects on the reaction yield. The electron withdrawing substituent, NO2 group 3b, on the aromatic aldehydes gave a good yield more than the electron donating substituent, OH group 3c. The electron deficient on the carbon atom of the aldehydic group may increase the interaction of the Lewis acid (Cu(OTf)2) and the Lewis base (imine nitrogen), and accordingly, facilitate the formation of imine easily, which is attacked by the nucleophilic phosphite species to give the α- aminophosphonates. Conclusion: The newly synthesized compounds exhibit a remarkable inhibition of the growth of Grampositive, Gram-negative bacteria and fungi at low concentrations. The cytotoxicity of the synthesized compounds showed a significant cytotoxicity against the liver cancer cell line (HepG 2). Also, it was shown from the quantum chemical calculations that the electron-withdrawing substituent increases the biological activity of the α-aminophosphonates more than the electron donating group which was in a good agreement with the experimental results. Also, a good agreement between the experimental FT-IR and the calculated one was found.

Evaluation of Chemotherapeutic Activity of the Selected Bases’ Analogues of Nucleic Acids Supported by ab initio Various Quantum Chemical Calculations

2020 ◽  
Vol 16 (2) ◽  
pp. 93-103 ◽  
Author(s):  
Piotr Kawczak ◽  
Leszek Bober ◽  
Tomasz Bączek
Keyword(s):  
Biological Activity ◽  
Nucleic Acids ◽  
Ab Initio ◽  
Quantum Chemical Calculations ◽  
Quantum Chemical ◽  
Structural Parameters ◽  
Principal Component ◽  
Polarizable Continuum Model ◽  
Activity Data ◽  
Qsar Models

Background: Pharmacological and physicochemical classification of bases’ selected analogues of nucleic acids is proposed in the study. Objective: Structural parameters received by the PCM (Polarizable Continuum Model) with several types of calculation methods for the structures in vacuo and in the aquatic environment together with the huge set of extra molecular descriptors obtained by the professional software and literature values of biological activity were used to search the relationships. Methods: Principal Component Analysis (PCA) together with Factor Analysis (FA) and Multiple Linear Regressions (MLR) as the types of the chemometric approach based on semi-empirical ab initio molecular modeling studies were performed. Results: The equations with statistically significant descriptors were proposed to demonstrate both the common and differentiating characteristics of the bases' analogues of nucleic acids based on the quantum chemical calculations and biological activity data. Conclusion: The obtained QSAR models can be used for predicting and explaining the activity of studied molecules.

Schistosomal Sulfotransferase Interaction with Oxamniquine Involves Hybrid Mechanism of Induced-fit and Conformational Selection

2020 ◽  
Vol 16 (4) ◽  
pp. 451-459 ◽  
Author(s):  
Fortunatus C. Ezebuo ◽  
Ikemefuna C. Uzochukwu
Keyword(s):  
Molecular Dynamics ◽  
Amino Acid ◽  
Binding Energy ◽  
Binding Site ◽  
Conformational Dynamics ◽  
Side Chain ◽  
Amino Acid Residues ◽  
Conformational Selection ◽  
Hybrid Mechanism ◽  
Dynamics Simulations

Background: Sulfotransferase family comprises key enzymes involved in drug metabolism. Oxamniquine is a pro-drug converted into its active form by schistosomal sulfotransferase. The conformational dynamics of side-chain amino acid residues at the binding site of schistosomal sulfotransferase towards activation of oxamniquine has not received attention. Objective: The study investigated the conformational dynamics of binding site residues in free and oxamniquine bound schistosomal sulfotransferase systems and their contribution to the mechanism of oxamniquine activation by schistosomal sulfotransferase using molecular dynamics simulations and binding energy calculations. Methods: Schistosomal sulfotransferase was obtained from Protein Data Bank and both the free and oxamniquine bound forms were subjected to molecular dynamics simulations using GROMACS-4.5.5 after modeling it’s missing amino acid residues with SWISS-MODEL. Amino acid residues at its binding site for oxamniquine was determined and used for Principal Component Analysis and calculations of side-chain dihedrals. In addition, binding energy of the oxamniquine bound system was calculated using g_MMPBSA. Results: The results showed that binding site amino acid residues in free and oxamniquine bound sulfotransferase sampled different conformational space involving several rotameric states. Importantly, Phe45, Ile145 and Leu241 generated newly induced conformations, whereas Phe41 exhibited shift in equilibrium of its conformational distribution. In addition, the result showed binding energy of -130.091 ± 8.800 KJ/mol and Phe45 contributed -9.8576 KJ/mol. Conclusion: The results showed that schistosomal sulfotransferase binds oxamniquine by relying on hybrid mechanism of induced fit and conformational selection models. The findings offer new insight into sulfotransferase engineering and design of new drugs that target sulfotransferase.

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