Multiple active zones in hybrid QM/MM molecular dynamics simulations for large biomolecular systems

A new QM/MM molecular dynamics approach that can deal with the dynamics of large real systems involving several simultaneous active zones is presented. Multiple, unconnected but interacting quantum regions are treated independently in an ordinary QM/MM approach but in a manner which converges to a unique simulation. The multiple active zones in the hybrid QM/MM molecular dynamics methodology (maz-QM/MM MD) involve molecular dynamics that is driving the whole simulation with several parallel executions of energy gradients within the QM/MM approach that merge into each MD step. The Ewald-summation method is used to incorporate long-range electrostatic interactions among the active zones in conjunction with periodic boundary conditions. To illustrate and ascertain capabilities and limitations, we present several benchmark calculations using this approach. Our results show that the maz-QM/MM MD method is able to provide simultaneous treatment of several active zones of very large proteins such as the Cu-4His-¿C* cage, a self-assembly of a 24-mer cage-like protein ferritinPeer ReviewedPostprint (published version

Massive quantum regions for simulations on bio-nanomaterials: synthetic ferritin nanocages

QM/MM molecular dynamics simulations on the 4His-DC* protein cage have been performed using multiple active zones (up to 86 quantum regions). The regulation and nanocage stability exerted by the divalent transitionmetal ions in the monomer-to-cage conversion have been understood by comparing high level quantum trajectories obtained using Cu2+ and Ni2+ coordination ions.Peer ReviewedPostprint (published version

Solvent effects on the properties of hyperbranched polythiophenes

The structural and electronic properties of all-thiophene dendrimers and dendrons in solution have been evaluated using very different theoretical approaches based on quantum mechanical (QM) and hybrid QM/molecular mechanics (MM) methodologies: (i) calculations on minimum energy conformations using an implicit solvation model in combination with density functional theory (DFT) or time-dependent DFT (TD-DFT) methods; (ii) hybrid QM/MM calculations, in which the solute and solvent molecules are represented at the DFT level as point charges, respectively, on snapshots extracted from classical molecular dynamics (MD) simulations using explicit solvent molecules, and (iii) QM/MM-MD trajectories in which the solute is described at the DFT or TD-DFT level and the explicit solvent molecules are represented using classical force-fields. Calculations have been performed in dichloromethane, tetrahydrofuran and dimethylformamide. A comparison of the results obtained using the different approaches with the available experimental data indicates that the incorporation of effects associated with both the conformational dynamics of the dendrimer and the explicit solvent molecules is strictly necessary to satisfactorily reproduce the properties of the investigated systems. Accordingly, QM/MM-MD simulations are able to capture such effects providing a reliable description of electronic properties–conformational flexibility relationships in all-Th dendrimers.Peer ReviewedPostprint (author's final draft

Introduction to molecular modeling of materials in an undergraduate engineering degree

Molecular modeling is a chemistry tool that has been widely used in the last decades to mainly support the basic concepts of general chemistry and organic chemistry, in both undergraduate programs of basic sciences and some technological careers. Despite its use, except in some very specific cases, it has been extensively employed as illustrative examples of the chemical concepts that were being demonstrated. Despite the numerous existing applications to comprehend the phenomena behind the development of new materials and biomedicine, it is difficult to find a conceptual introduction of molecular modeling applied to specific problems on the modern engineeries within the undergraduate programs. In the present work, it will be shown the introduction and adaptation of molecular modeling concepts within a new optional course for students coming from materials engineering, chemical engineering and biomedicine engineeries. Different approaches to problem-based and small project-based learning are presented to encourage the scientific spirit of students using techniques of molecular modeling that had not been visited throughout their studies and, thus, to discover their potential appliacation in a more specialized context

Molecular dynamics study on the Apo- and Holo-forms of 5-lipoxygenase

Lipoxygenases (LOXs) are nonheme iron-containing enzymes catalyzing the dioxygenation of polyunsaturated fatty acids. LOX catalytic activity depends on the presence of iron in the active site and the iron removal is also able to affect the membrane binding properties of the enzyme. Leukotrienes biosynthesis is initiated by the action of 5-LOX at the level of nuclear membrane and the mechanism of enzyme-membrane interaction is thought to involve structural flexibility and conformational changes at the level of the protein tertiary structure. In this study, we have analyzed by molecular dynamics simulations the conformational changes induced by iron removal in 5-LOX. The data indicate that the degree of enzyme flexibility is related to the presence of iron into the active site that is able to stabilize the protein increasing its rigidity. These findings provide further evidence that the conformation and the functional activity of LOXs is tuned by the presence of iron at the active site, suggesting new approaches for the design of enzyme inhibitors.Peer ReviewedPostprint (author's final draft

Study on the control of porosity in films of polythiophene derivatives

Conducting polymers typically exhibit different oxidation states, which are easily interchangeable among them by means of the application of an electrical potential. In this work, we present a theoretical and experimental study to regulate the pore size of poly(3,4-ethylenedioxythiophene) (PEDOT) films doped with ClO4- ions by controlling their oxidation state. More specifically, different bulk and surface PEDOT models have been evaluated applying 2D- and 3-D periodic boundary conditions to density functional theory calculations. In highly oxidized PEDOT films, calculations predict that the incorporation of dopant ions increases the separation between neighboring chains, causing a structural re-organization. Thus, the calculated average pore size, which has been modeled as a structural defect in 2D surface models, increases by 15.1%. This increment is consistent with experimental measures of the nanopore size in PEDOT films with enhanced porosity, which reflect a difference of 25.2% between the oxidized and reduced forms. This superficial phenomenon could easily be used to retain and release controlled drugs through the application of different electric potentialsPeer ReviewedPostprint (author's final draft

Recent progress in biomedical sensors based on conducting polymer hydrogels

Biosensors are increasingly taking a more active role in health science. The current needs for the constant monitoring of biomedical signals, as well as the growing spending on public health, make it necessary to search for materials with a combination of properties such as biocompatibility, electroactivity, resorption, and high selectivity to certain bioanalytes. Conducting polymer hydrogels seem to be a very promising materials, since they present many of the necessary properties to be used as biosensors. Furthermore, their properties can be shaped and enhanced by designing conductive polymer hydrogel-based composites with more specific functionalities depending on the end application. This work will review the recent state of the art of different biological hydrogels for biosensor applications, discuss the properties of the different components alone and in combination, and reveal their high potential as candidate materials in the fabrication of all-organic diagnostic, wearable, and implantable sensor devices.Peer ReviewedPostprint (published version

Free-standing, flexible nanofeatured polymeric films prepared by spin-coating and anodic polymerization as electrodes for supercapacitors

Flexible and self-standing multilayered films made of nanoperforated poly(lactic acid) (PLA) layers separated by anodically polymerized poly(3,4-ethylenedioxythiophene) (PEDOT) conducting layers have been prepared and used as electrodes for supercapacitors. The influence of the external layer has been evaluated by comparing the charge storage capacity of four- and five-layered films in which the external layer is made of PEDOT (PLA/PEDOT/PLA/PEDOT) and nanoperforated PLA (PLA/PEDOT/PLA/PEDOT/PLA), respectively. In spite of the amount of conducting polymer is the same for both four- and five-layered films, they exhibit significant differences. The electrochemical response in terms of electroactivity, areal specific capacitance, stability, and coulombic efficiency was greater for the four-layered electrodes than for the five-layered ones. Furthermore, the response in terms of leakage current and self-discharge was significantly better for the former electrodes than for the latter ones.Postprint (author's final draft

Recent advances in poly(N-isopropylacrylamide) hydrogels and derivatives as promising materials for biomedical and engineering emerging applications

Temperature-sensitive (thermosensitive) hydrogels, which are part of the family of stimulus-sensitive hydrogels, consist of water-filled polymer networks that display a temperature-dependent degree of swelling. Thermosensitive hydrogels, which can undergo phase transition or swell/deswell as temperature changes, have great potential in various technological and biomedical purposes for a number of reasons: their temperature response is revesible, hydrogels are stable and easy to prepare, they can be biocompatible and also be suitably combined with other organic and inorganic materials, resulting in new materials with outstanding properties. Among thermosensitive hydrogels poly(N-isopropylacrylamide) (PNIPAAm) is the most extensively studied because it brings together the best properties of these materials. Consequently, in the last few years a wide number of applications and new chemical processes to prepare PNIPAAm and their derivatives are being proposed. The objective of this review is to summarize fundamentals of thermosensitive hydrogels and recent advances in preparation and both technological and biomedical applications of thermosensitive hydrogel, with special focus on PNIPAAm and their derivatives. Special attention has been given to the discussion of challenges and future research perspectives based on new horizons not yet considered.Peer ReviewedPostprint (published version

Examining the compatibility of collagen and a polythiophene derivative for the preparation of bioactive platforms

Fundamental characteristics of bioactive platforms based on biocomposites of poly(3,4-ethylenedioxythiophene) (PEDOT) and collagen, named P(EDOT:CLG), have been examined using an experimental–computational approach. The protein affects both the morphology and electrochemical activity of PEDOT. Specifically, P(EDOT:CLG) shows spherical-like nodules that have been attributed to the collagen rod aggregates organized in phases separated from that of PEDOT. This phase separation results in a reduction of the ability to exchange charge reversibly, even though collagen stabilizes the PEDOT matrix from electrochemical degradation. On the other hand, viability assays indicate that the bioactivity of P(EDOT:CLG) is significantly higher than that of PEDOT in terms of cellular adhesion and proliferation. Thus, the biocomposite promotes the formation of 3D biostructures formed by the superposition of cellular monolayers, mimicking the growth of biological tissues. In order to gain microscopic information about the formation of specific interactions between PEDOT and collagen molecules in the biocomposite, quantum mechanical calculations on complexes formed by their building blocks have been performed in different environments (i.e. vacuum, chloroform and aqueous solution). Results evidence the important role played by non-conventional C–HO hydrogen bonds, which is consistent with previous findings on complexes involving DNA and dopamine. The environment affects considerably the binding energy, which decreases with increasing polarity of the environment. However, in all environments the repeating units of PEDOT form stronger interactions with L-hydroxyproline than with L-proline. On the other hand, intermolecular interaction patterns predicted using implicit and explicit solvation models present a remarkable agreement and have been identified by visualizing the reduced electron density gradient.Peer ReviewedPostprint (published version