ABSTRACT
The structure of a dendrimer exhibits a large number of internal and superficial cavities, which can be exploited, to capture and deliver small organic molecules, enabling their use in drug delivery. Structure-based modeling and quantum mechanical studies can be used to accurately understand the interactions between functionalized dendrimers and molecules of pharmaceutical and industrial interest. In this study, we implemented a Metropolis Monte Carlo algorithm to calculate the interaction energy of dendrimer-drug complexes, which can be used for in silico prediction of dendrimer-drug affinity. Initially, a large-scale sampling of different dendrimer-drug conformations was generated using Euler angles. Then, each conformation was distributed on different nodes of a GRID computational system, where its interaction energy was calculated by semiempirical quantum mechanical methods. These energy calculations were performed for four different nonsteroidal anti-inflammatory drugs, each showing different affinities for the PAMAM-G4 dendrimer. The affinities were also characterized experimentally by using Cooks' kinetic method to calculate PAMAM-drug dissociation constants. The quantitative structure-activity relationship between the interaction energies and dissociation constants showed statistical correlations with r(2) > 0.9.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemistry , Dendrimers/chemistry , Drug Carriers/chemistry , Computer Simulation , Models, Molecular , Monte Carlo Method , Nylons/chemistry , Spectrometry, Mass, Electrospray Ionization , Tandem Mass Spectrometry , ThermodynamicsABSTRACT
After the progress made during the genomics era, bioinformatics was tasked with supporting the flow of information generated by nanobiotechnology efforts. This challenge requires adapting classical bioinformatic and computational chemistry tools to store, standardize, analyze, and visualize nanobiotechnological information. Thus, old and new bioinformatic and computational chemistry tools have been merged into a new sub-discipline: nanoinformatics. This review takes a second look at the development of this new and exciting area as seen from the perspective of the evolution of nanobiotechnology applied to the life sciences. The knowledge obtained at the nano-scale level implies answers to new questions and the development of new concepts in different fields. The rapid convergence of technologies around nanobiotechnologies has spun off collaborative networks and web platforms created for sharing and discussing the knowledge generated in nanobiotechnology. The implementation of new database schemes suitable for storage, processing and integrating physical, chemical, and biological properties of nanoparticles will be a key element in achieving the promises in this convergent field. In this work, we will review some applications of nanobiotechnology to life sciences in generating new requirements for diverse scientific fields, such as bioinformatics and computational chemistry.
Subject(s)
Biological Science Disciplines , Computational Biology/trends , Medical Informatics/methods , Microchemistry , Nanotechnology/trends , Computer Simulation , Humans , Medical Informatics/trends , Models, MolecularABSTRACT
Polyamidoamine (PAMAM) dendrimers and water-soluble 3-mercaptopropionic acid (MPA)-capped CdSe quantum dots (QDs) were combined to produce a new gel containing supramolecular complexes of QDs/PAMAM dendrimers. The formation of the QDs/PAMAM supramolecular complexes was confirmed by high resolution electron microscopy and Fourier transform infrared (FTIR) analyses. Molecular dynamics simulations corroborated the structure of the new QDs/PAMAM-based supramolecular compound. Finally, on the basis of the prominent fluorescent properties of the supramolecular complexes, PAMAM dendrimer was functionalized with folic acid to produce a new QDs/PAMAM-folate derivative that showed an efficient and selective performance as a marker for gastric cancer cells.
Subject(s)
Diagnostic Imaging/methods , Quantum Dots , Stomach Neoplasms/diagnosis , Cell Line, Tumor , Dendrimers/chemistry , Diagnostic Imaging/instrumentation , Folic Acid/chemistry , HumansABSTRACT
After the progress made during the genomics era, bioinformatics was tasked with supporting the flow of information generated by nanobiotechnology efforts. This challenge requires adapting classical bioinformatic and computational chemistry tools to store, standardize, analyze, and visualize nanobiotechnological information. Thus, old and new bioinformatic and computational chemistry tools have been merged into a new sub-discipline: nanoinformatics. This review takes a second look at the development of this new and exciting area as seen from the perspective of the evolution of nanobiotechnology applied to the life sciences. The knowledge obtained at the nano-scale level implies answers to new questions and the development of new concepts in different fields. The rapid convergence of technologies around nanobiotechnologies has spun off collaborative networks and web platforms created for sharing and discussing the knowledge generated in nanobiotechnology. The implementation of new database schemes suitable for storage, processing and integrating physical, chemical, and biological properties of nanoparticles will be a key element in achieving the promises in this convergent field. In this work, we will review some applications of nanobiotechnology to life sciences in generating new requirements for diverse scientific fields, such as bioinformatics and computational chemistry.
Subject(s)
Humans , Biological Science Disciplines , Computational Biology/trends , Microchemistry , Medical Informatics/methods , Nanotechnology/trends , Computer Simulation , Models, Molecular , Medical Informatics/trendsABSTRACT
Several 1:1, 1:2, and 2:2 complexes between BF3 and CH3OH (Met), CH3COOH (AcA), (CH3)2O (DME), (CH3CH2)2O (DEE), and (CH2)2O (EOX) have been studied using ab initio (MP2) and density functional theory (DFT) (PBE, B3LYP) methods and the 6-311++G(3df,2pd) basis set. Geometrical structures and vibrational frequencies are reported, in most cases, for the first time. A detailed comparison of the vibrational frequencies for the O...BF3 vibrational modes, as well as for the nu(OH) band in the methanol and acetic acid complexes with BF3, is performed, and the theoretical frequency shifts are compared with the available experimental information. Thermochemical properties are calculated by employing counterpoise correction to alleviate the basis set superposition error. The DFT enthalpy of complexation of the 1:1 complexes results in the order of stability (AcA)2>AcA:BF3>DEE:BF3>DME:BF3>Met:BF3>EOX:BF3>(Met)2; in contrast, MP2 shows the noticeable difference that the AcA:BF3 complex is much less stable (similar to Met:BF3). The order of stability shows that, even though acetic acid prefers dimerization to complexation with BF3, the case is exactly the opposite for methanol. In both cases, the interaction of BF3 with the dimer gives rise to very stable trimers. However, in contrast to the interaction of BF3 with the methanol dimer being stronger than that with the monomer, the interaction of BF3 with the acetic acid dimer is weaker than that with the monomer. The relative strength of the complexes, discussed in the context of BF3-catalyzed ring opening of epoxides, suggests that the effect of the catalyst in a nonprotogenic solvent should be more properly ascribed to activation of the nucleophile instead of activation of the epoxide.
Subject(s)
Acetic Acid/chemistry , Boranes/chemistry , Epoxy Compounds/chemistry , Ether/chemistry , Ethylene Oxide/chemistry , Methanol/chemistry , Methyl Ethers/chemistry , Cyclization , Models, Molecular , Quantum TheoryABSTRACT
Immune evasion strategies often shape the immunogenicity of parasite components. We recently found that the N-terminal extension of the major subunit of Echinococcus granulosus antigen B (AgB), the causative agent of hydatid disease, concentrates the immunoreactive B cell epitopes of the native molecule. The nature of this immunodominance was analyzed using four monoclonal antibodies (mAbs) defining overlapping epitopes in this region of the AgB molecule. The minimal epitope requirements of these mAbs were determined using phage display peptide libraries. The consensus sequences isolated with the mAbs, and alanine replacement analysis with synthetic peptides mapped the relevant molecular contacts within a short stretch corresponding to residues 17-24 of the AgB major subunit. Substitution of two critical residues within this stretch produced a dramatic loss of antigenicity, as determined by using patient sera. The circular dichroism spectra of the antigen, together with the distribution of the contact residues, suggest that this region adopts an amphipathic alpha-helix structure that clusters the contact residues on its polar side. To provide further insight in the interpretation of the structure activity relationships for this immunoreactive region of E. granulosus AgB, we developed a model for the N-terminal extension of the AgB major subunit, which helps to rationalize our data.
Subject(s)
Echinococcus/immunology , Helminth Proteins , Lipoproteins/chemistry , Amino Acid Sequence , Animals , Enzyme-Linked Immunosorbent Assay , Models, Molecular , Molecular Sequence Data , Sequence Homology, Amino AcidABSTRACT
The crystal structure of Escherichia coli phosphoenolpyruvate (PEP) carboxykinase shows Lys213 is one of the ligands of enzyme-bound Mn2+ [Nat. Struct. Biol. 4 (1997) 990]. The direct coordination of Mn2+ by N(epsilon) of Lys213 is only consistent with a neutral (uncharged) Lys213, suggesting a low pKa for this residue. This work shows, through theoretical calculations and experimental analyses on homologous Saccharomyces cerevisiae PEP carboxykinase, how the microenvironment affects Mn2+ binding and the protonation state of Lys213. We show that Glu284, a residue close to Lys212, is required for correct protonation states of Lys212 and Lys213, and for Mn2+ binding. deltaG and deltaH values for the proton reorganization processes were calculated to analyze the energetic stability of the two different protonation states of Lys212 and Lys213 in wild-type and Glu284Gln S. cerevisiae PEP carboxykinase. Calculations were done using two modeling approaches, ab-initio density functional calculations and free energy perturbation (FEP) calculations. Both methods suggest that Lys212 must be protonated and Lys213 neutral in the wild-type enzyme. On the other hand, the calculations on the Glu284Gln mutant suggest a more stable neutral Lys212 and protonated Lys213. Experimental measurements showed 3 orders of magnitude lower activity and a threefold increase in Km for Mn2+ for Glu284Gln S. cerevisiae PEP carboxykinase when compared to wild type. The data here presented suggest that Glu284 is required for Mn2+ binding by S. cerevisiae PEP carboxykinase. We propose that Glu284 modulates the pKa value of Lys213 through electrostatic effects mediated by