A computational investigation of the interaction of the collagen molecule with hydroxyapatite

This thesis presents the results of computer simulation studies of the interaction of the predominant molecules in the collagen protein with the hydroxyapatite mineral. Using a combination of computational techniques, quantum-mechanical methods based on the density functional theory (DFT) and molecular dynamics simulations based on interatomic potentials, we have investigated the interface between the collagen protein and the apatite mineral. First we have employed electronic structure techniques (DFT) to study a range of different binding modes of the amino acids glycine, proline and hydroxyproline, which are major constituents of the collagen I protein, at two important hydroxyapatite surfaces, (0001) and (0110) . We have performed full geometry optimizations of the hydroxyapatite surface with adsorbed amino acid molecules to obtain the optimum substrate/adsorbate structures and interaction energies. We have also used DFT to investigate the binding of a series of representative peptides containing hydrophobic side groups (proline), uncharged polar side groups (glycine and hydroxyproline), and charged polar side groups (lysine and hydroxylysine) to the hydroxyapatite (0001) and (0110) surfaces. This selection of adsorbates has given us the opportunity to study separately the interactions of the carboxylic acid and amine functional groups, as well as the effect of hydroxylation and the charges of the side group, on the strength of interaction with the surfaces. We have also investigated the same systems in an aqueous environment using classical molecular dynamics simulation, where we have calculated the energies and geometries of adsorption of the peptide at the surfaces of hydroxyapatite in competition with pre-adsorbed water. Finally, we have studied the onset of nucleation of the hydroxyapatite mineral at an entire collagen molecule in aqueous solution

Theoretical Description of the Role of Halides, Silver, and Surfactants on the Structure of Gold Nanorods

Density functional theory simulations including dispersion provide an atomistic description of the role of different compounds in the synthesis of gold-nanorods. Anisotropy is caused by the formation of a complex between the surfactant, bromine, and silver that preferentially adsorbs on some facets of the seeds, blocking them from further growth. In turn, the nanorod structure is driven by the perferential adsorption of the surfactant, which induces the appearance of open {520} lateral facets

Effect of Linker Distribution in the Photocatalytic Activity of Multivariate Mesoporous Crystals

The use of Metal-Organic Frameworks as crystalline matrices for the synthesis of multiple component or multivariate solids by the combination of different linkers into a single material has emerged as a versatile route to tailor the properties of single-component phases or even access new functions. This approach is particularly relevant for Zr6-MOFs due to the synthetic flexibility of this inorganic node. However, the majority of materials are isolated as polycrystalline solids, which are not ideal to decipher the spatial arrangement of parent and exchanged linkers for the formation of homogeneous structures or heterogeneous domains across the solid. Here we use high-throughput methodologies to optimize the synthesis of single crystals of UiO-68 and UiO-68-TZDC, a photoactive analogue based on a tetrazine dicarboxylic derivative. The analysis of the single linker phases reveals the necessity of combining both linkers to produce multivariate frameworks that combine efficient light sensitization, chemical stability, and porosity, all relevant to photocatalysis. We use solvent-assisted linker exchange reactions to produce a family of UiO-68-TZDC% binary frameworks, which respect the integrity and morphology of the original crystals. Our results suggest that the concentration of TZDC in solution and the reaction time control the distribution of this linker in the sibling crystals for a uniform mixture or the formation of core-shell domains. We also demonstrate how the possibility of generating an asymmetric distribution of both linkers has a negligible effect on the electronic structure and optical band gap of the solids but controls their performance for drastic changes in the photocatalytic activity toward proton or methyl viologen reduction.This work was supported by the EU (ERC Stg Chem-fs-MOF 714122) and Spanish government (CTQ2017-83486-P, RTI2018-098568-A-I00, RYC-2016-1981, CEX2019-000919-M, PID2019-106383GB-C44/AEI/10.13039/501100011033 and RTI2018-098568-A-I00). B.L.-B. thanks the Spanish government for a FPU (FPU16/04162). S.T. thanks the Spanish government for a Ramón y Cajal Fellowship (RYC-2016-60719817). N.M.P. thanks the European Union for a Marie Skłodowska-Curie Global Fellowship (H2020-MSCA-IF-2016-GF-749359-EnanSET). J.G.P. thanks to the SIDIX at Servicios Generales de Apoyo a la Investigación (SEGAI) at La Laguna University. We also thank BSC-RES for computational resources (QS-2020-2-0024) and the University of Valencia for research facilities (Tirant and NANBIOSIS).Peer reviewe

Heterometallic Titanium-Organic Frameworks as Dual Metal Catalysts for Synergistic Non-Buffered Hydrolysis of Nerve Agent Simulants

Heterometallic metal-organic frameworks (MOFs) can offer important advantages over their homometallic counterparts to enable targeted modification of their adsorption, structural response, electronic structure, or chemical reactivity. However, controlling metal distribution in these solids still remains a challenge. The family of mesoporous titanium-organic frameworks, MUV-101(M), displays heterometallic TiM2 nodes assembled from direct reaction of Ti(IV) and M(II) salts. We use the degradation of nerve agent simulants to demonstrate that only TiFe2 nodes are capable of catalytic degradation in non-buffered conditions. By using an integrative experimental-computational approach, we rationalize how the two metals influence each other, in this case, for a synergistic mechanism reminiscent of bimetallic enzymes. Our results highlight the importance of controlling metal distribution at an atomic level to span the interest of heterometallic MOFs to a broad scope of cascade or tandem reactions. Summary Mixed-metal or heterometallic metal-organic frameworks (MOFs) are gaining importance as a route to produce materials with increasing chemical and functional complexities. We report a family of heterometallic titanium frameworks, MUV-101(M), and use them to exemplify the advantages of controlling metal distribution across the framework in heterogeneous catalysis by exploring their activity toward the degradation of a nerve agent simulant of Sarin gas. MUV-101(Fe) is the only pristine MOF capable of catalytic degradation of diisopropyl-fluorophosphate (DIFP) in non-buffered aqueous media. This activity cannot be explained only by the association of two metals, but to their synergistic cooperation, to create a whole that is more efficient than the simple sum of its parts. Our simulations suggest a dual-metal mechanism reminiscent of bimetallic enzymes, where the combination of Ti(IV) Lewis acid and Fe(III)–OH Brönsted base sites leads to a lower energy barrier for more efficient degradation of DIFP in absence of a base.Financial support for this work was provided by the Marie Skłodowska-Curie Global Fellowships (749359-EnanSET, N.M.P) within the European Union research and innovation framework programme (2014-2020

Homochiral Metal-Organic Frameworks for Enantioselective Separations in Liquid Chromatography

Selective separation of enantiomers is a substantial challenge for the pharmaceutical industry. Chromatography on chiral stationary phases is the standard method, but at a very high cost for industrial-scale purification owing to the high cost of the chiral stationary phases. Typically, these materials are poorly robust, expensive to manufacture and often too specific for a single desired substrate, lacking desirable versatility across different chiral analytes. Here we disclose a porous, robust homochiral metal-organic framework (MOF), TAMOF-1, built from copper(II) and an affordable linker prepared from natural L-histidine. TAMOF-1 has shown to be able to separate a variety of model racemic mixtures, including drugs, in a wide range of solvents of different polarity, outperforming several commercial chiral columns for HPLC separations. Although not exploited in the present article, it is worthy to mention that the preparation of this new material is scalable to the multikilogram scale, opening unprecedented possibilities for low-energy chiral separation at the industrial scale

Molecular mechanics of mineralized collagen fibrils in bone

Bone is a natural composite of collagen protein and the mineral hydroxyapatite. The structure of bone is known to be important to its load-bearing characteristics, but relatively little is known about this structure or the mechanism that govern deformation at the molecular scale. Here we perform full-atomistic calculations of the three-dimensional molecular structure of a mineralized collagen protein matrix to try to better understand its mechanical characteristics under tensile loading at various mineral densities. We find that as the mineral density increases, the tensile modulus of the network increases monotonically and well beyond that of pure collagen fibrils. Our results suggest that the mineral crystals within this network bears up to four times the stress of the collagen fibrils, whereas the collagen is predominantly responsible for the material’s deformation response. These findings reveal the mechanism by which bone is able to achieve superior energy dissipation and fracture resistance characteristics beyond its individual constituents.United States. Office of Naval Research (N000141010562)United States. Army Research Office (W991NF-09-1-0541)United States. Army Research Office (W911NF-10-1-0127)National Science Foundation (U.S.) (CMMI-0642545

Anisotropic diffusion of water molecules in hydroxyapatite nanopores

Funded by EPSRC Grant EP/K000128/1

Roles of Electrostatics and Conformation in Protein-Crystal Interactions

In vitro studies have shown that the phosphoprotein osteopontin (OPN) inhibits the nucleation and growth of hydroxyapatite (HA) and other biominerals. In vivo, OPN is believed to prevent the calcification of soft tissues. However, the nature of the interaction between OPN and HA is not understood. In the computational part of the present study, we used molecular dynamics simulations to predict the adsorption of 19 peptides, each 16 amino acids long and collectively covering the entire sequence of OPN, to the {100} face of HA. This analysis showed that there is an inverse relationship between predicted strength of adsorption and peptide isoelectric point (P<0.0001). Analysis of the OPN sequence by PONDR (Predictor of Naturally Disordered Regions) indicated that OPN sequences predicted to adsorb well to HA are highly disordered. In the experimental part of the study, we synthesized phosphorylated and non-phosphorylated peptides corresponding to OPN sequences 65–80 (pSHDHMDDDDDDDDDGD) and 220–235 (pSHEpSTEQSDAIDpSAEK). In agreement with the PONDR analysis, these were shown by circular dichroism spectroscopy to be largely disordered. A constant-composition/seeded growth assay was used to assess the HA-inhibiting potencies of the synthetic peptides. The phosphorylated versions of OPN65-80 (IC50 = 1.93 µg/ml) and OPN220-235 (IC50 = 1.48 µg/ml) are potent inhibitors of HA growth, as is the nonphosphorylated version of OPN65-80 (IC50 = 2.97 µg/ml); the nonphosphorylated version of OPN220-235 has no measurable inhibitory activity. These findings suggest that the adsorption of acidic proteins to Ca2+-rich crystal faces of biominerals is governed by electrostatics and is facilitated by conformational flexibility of the polypeptide chain

Controlled synthesis of monodisperse gold nanorods with different aspect ratios in the presence of aromatic additives

This paper reports the synthesis of monodisperse gold nanorods (GNRs) via a simple seeded growth approach in the presence of different aromatic additives, such as 7-bromo-3-hydroxy-2-naphthoic acid (7-BrHNA), 3-hydroxy-2-naphthoic acid (HNA), 5-bromosalicylic acid (5-BrSA), salicylic acid (SA) or phenol (PhOH). Effects of the aromatic additives and hydrochloric acid (HCl) on the structure and optical properties of the synthesized GNRs were investigated. The longitudinal surface plasmon resonance (LSPR) peak wavelength of the resulting GNRs was found to be dependent on the aromatic additive in the following sequence: 5-BrSA (778 nm) > 7-BrHNA (706 nm) > SA (688 nm) > HNA (676 nm) > PhOH (638 nm) without addition of HCl, but this was changed to 7-BrHNA (920 nm) > SA (890 nm) > HNA (872 nm) > PhOH (858 nm) > 5-BrSA (816 nm) or 7-BrHNA (1005 nm) > PhOH (995 nm) > SA (990 nm) > HNA (980 nm) > 5-BrSA (815 nm) with the addition of HCl or HNO3 respectively. The LSPR peak wavelength was increased with the increasing concentration of 7-BrHNA without HCl addition, however, there was a maximum LSPR peak wavelength when HCl was added. Interestingly, the LSPR peak wavelength was also increased with amount of HCl added. The results presented here thus established a simple approach to synthesize monodisperse GNRs of different LSPR wavelength

A computational investigation of the interaction of the collagen molecule with hydroxyapatite.

This thesis presents the results of computer simulation studies of the interaction of the predominant molecules in the collagen protein with the hydroxyapatite mineral. Using a combination of computational techniques, quantum-mechanical methods based on the density functional theory (DFT) and molecular dynamics simulations based on interatomic potentials, we have investigated the interface between the collagen protein and the apatite mineral. First we have employed electronic structure techniques (DFT) to study a range of different binding modes of the amino acids glycine, proline and hydroxyproline, which are major constituents of the collagen I protein, at two important hydroxyapatite surfaces, (0001) and (0110) . We have performed full geometry optimizations of the hydroxyapatite surface with adsorbed amino acid molecules to obtain the optimum substrate/adsorbate structures and interaction energies. We have also used DFT to investigate the binding of a series of representative peptides containing hydrophobic side groups (proline), uncharged polar side groups (glycine and hydroxyproline), and charged polar side groups (lysine and hydroxylysine) to the hydroxyapatite (0001) and (0110) surfaces. This selection of adsorbates has given us the opportunity to study separately the interactions of the carboxylic acid and amine functional groups, as well as the effect of hydroxylation and the charges of the side group, on the strength of interaction with the surfaces. We have also investigated the same systems in an aqueous environment using classical molecular dynamics simulation, where we have calculated the energies and geometries of adsorption of the peptide at the surfaces of hydroxyapatite in competition with pre-adsorbed water. Finally, we have studied the onset of nucleation of the hydroxyapatite mineral at an entire collagen molecule in aqueous solution.