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Distance-based configurational entropy of proteins from molecular dynamics simulations
Federico Fogolari, Alessandra Corazza, Sara Fortuna, Miguel Angel Soler, Bryan VanSchouwen, Giorgia Brancolini, Stefano Corni, Giuseppe Melacini, Gennaro Esposito, 2015, izvirni znanstveni članek

Opis: Estimation of configurational entropy from molecular dynamics trajectories is a difficult task which is often performed using quasi-harmonic or histogram analysis. An entirely different approach, proposed recently, estimates local density distribution around each conformational sample by measuring the distance from its nearest neighbors. In this work we show this theoretically well grounded the method can be easily applied to estimate the entropy from conformational sampling. We consider a set of systems that are representative of important biomolecular processes. In particular: reference entropies for amino acids in unfolded proteins are obtained from a database of residues not participating in secondary structure elements; the conformational entropy of folding of β2-microglobulin is computed from molecular dynamics simulations using reference entropies for the unfolded state; backbone conformational entropy is computed from molecular dynamics simulations of four different states of the EPAC protein and compared with order parameters (often used as a measure of entropy); the conformational and rototranslational entropy of binding is computed from simulations of 20 tripeptides bound to the peptide binding protein OppA and of β2-microglobulin bound to a citrate coated gold surface. This work shows the potential of the method in the most representative biological processes involving proteins, and provides a valuable alternative, principally in the shown cases, where other approaches are problematic.
Najdeno v: osebi
Ključne besede: entropy, protein, molecular dynamics, simulations, MD
Objavljeno: 12.10.2016; Ogledov: 2097; Prenosov: 158
.pdf Polno besedilo (2,40 MB)

In silico generation of peptides by replica exchange Monte Carlo: Docking-based optimization of maltose-binding-protein ligands
Anna Russo, Pasqualina Liana Scognamiglio, Rolando Pablo Hong Enriquez, Carlo Santambrogio, Rita Grandori, Daniela Marasco, Antonio Giordano, Giacinto Scoles, Sara Fortuna, 2015, izvirni znanstveni članek

Opis: Short peptides can be designed in silico and synthesized through automated techniques, making them advantageous and versatile protein binders. A number of docking-based algorithms allow for a computational screening of peptides as binders. Here we developed ex-novo peptides targeting the maltose site of the Maltose Binding Protein, the prototypical system for the study of protein ligand recognition. We used a Monte Carlo based protocol, to computationally evolve a set of octapeptides starting from a polialanine sequence. We screened in silico the candidate peptides and characterized their binding abilities by surface plasmon resonance, fluorescence and electrospray ionization mass spectrometry assays. These experiments showed the designed binders to recognize their target with micromolar affinity. We finally discuss the obtained results in the light of further improvement in the ex-novo optimization of peptide based binders.
Najdeno v: osebi
Ključne besede: peptides, docking, optimisation, computation, maltose binding protein, probe, ligand
Objavljeno: 12.10.2016; Ogledov: 1909; Prenosov: 82
.pdf Polno besedilo (4,27 MB)

Chelating effect in short polymers for the design of bidentate binders of increased affinity and selectivity
Sara Fortuna, Federico Fogolari, Giacinto Scoles, 2015, izvirni znanstveni članek

Opis: The design of new strong and selective binders is a key step towards the development of new sensing devices and effective drugs. Both affinity and selectivity can be increased through chelation and here we theoretically explore the possibility of coupling two binders through a flexible linker. We prove the enhanced ability of double binders of keeping their target with a simple model where a polymer composed by hard spheres interacts with a spherical macromolecule, such as a protein, through two sticky spots. By Monte Carlo simulations and thermodynamic integration we show the chelating effect to hold for coupling polymers whose radius of gyration is comparable to size of the chelated particle. We show the binding free energy of flexible double binders to be higher than that of two single binders and to be maximized when the binding sites are at distances comparable to the mean free polymer end-to-end distance. The affinity of two coupled binders is therefore predicted to increase non linearly and in turn, by targeting two non-equivalent binding sites, this will lead to higher selectivity.
Najdeno v: osebi
Ključne besede: chelation, polymer, multivalency, bidentate, free energy, thermodynamic integration, Monte Carlo
Objavljeno: 11.10.2016; Ogledov: 1935; Prenosov: 90
.pdf Polno besedilo (1,68 MB)

Accurate estimation of the entropy of rotation-translation probability distributions
Federico Fogolari, Cedrix Jurgal Dongmo Foumthuim, Sara Fortuna, Miguel Angel Soler, Alessandra Corazza, Gennaro Esposito, 2016, izvirni znanstveni članek

Opis: The estimation of rotational and translational entropies in the context of ligand binding has been the subject of long-time investigations. The high dimensionality (six) of the problem and the limited amount of sampling often prevent the required resolution to provide accurate estimates by the histogram method. Recently, the nearest-neighbor distance method has been applied to the problem, but the solutions provided either address rotation and translation separately, therefore lacking correlations, or use a heuristic approach. Here we address rotational–translational entropy estimation in the context of nearest-neighbor-based entropy estimation, solve the problem numerically, and provide an exact and an approximate method to estimate the full rotational–translational entropy.
Najdeno v: osebi
Ključne besede: entropy, probability distribution, molecular dynamics, nearest-neighbor
Objavljeno: 11.10.2016; Ogledov: 2143; Prenosov: 0
.pdf Polno besedilo (1,47 MB)

Phase behaviour of self-assembled monolayers controlled by tuning physisorbed and chemisorbed states: a lattice-model view
Sara Fortuna, David L. Cheung, Karen Johnston, 2016, izvirni znanstveni članek

Opis: The self-assembly of molecules on surfaces into 2D structures is important for the bottom-up fabrication of functional nanomaterials, and the self-assembledstructure depends on the interplay between molecule-molecule interactions and molecule-surface interactions. Halogenated benzene derivatives on platinum have been shown to have two distinct adsorption states: a physisorbed state and a chemisorbed state, and the interplay between the two can be expected to have a profound effect on the self-assembly and phase behaviour of these systems. We developed a lattice model that explicitly includes both adsorption states, with representative interactions parameterised using density functional theory calculations. This model was used in Monte Carlo simulations to investigate pattern formation of hexahalogenated benzene molecules on the platinumsurface. Molecules that prefer the physisorbed state were found to self-assemble with ease, depending on the interactions between physisorbed molecules. In contrast, molecules that preferentially chemisorb tend to get arrested in disordered phases. However, changing the interactions between chemisorbed and physisorbed molecules affects the phase behaviour. We propose functionalising molecules in order to tune their adsorption states, as an innovative way to control monolayer structure, leading to a promising avenue for directed assembly of novel 2D structures.
Najdeno v: osebi
Ključne besede: lattice model, hexagonal lattice, Monte Carlo, DFT, density functional theory, benzene, physisorption, chemisorption, halogenated
Objavljeno: 11.10.2016; Ogledov: 2340; Prenosov: 0
.pdf Polno besedilo (5,75 MB)

Oxalic acid adsorption states on the clean Cu(110) surface
Sara Fortuna, 2016, izvirni znanstveni članek

Opis: Carboxylic acids are known to assume a variety of configurations on metallic surfaces. In particular oxalic acid on the Cu(110) surface has been proposed to assume a number of upright configurations. Here we explore with DFT calculations the possible structures that oxalic acid can form on copper 110 at different protonation states, with particular attention at the possibility of forming structures composed of vertically standing molecules. In its fully protonated form it is capable of anchoring itself on the surface thanks to one of its hydrogen-free oxygens. We show the monodeprotonated upright molecule with two oxygens anchoring it on the surface to be the lowest energy conformation of a single oxalic molecules on the Cu(110) surface. We further show that it is possible for this configuration to form dense hexagonally arranged patterns in the unlikely scenario in which adatoms are not involved.
Najdeno v: osebi
Ključne besede: oxalic acid, oxalate, cu(110), copper, surface, adsorption, density functional theory, DFT
Objavljeno: 11.10.2016; Ogledov: 2180; Prenosov: 0
.pdf Polno besedilo (1,21 MB)

Molecular dynamics simulations and docking enable to explore the biophysical factors controlling the yields of engineered nanobodies
Ario de Marco, Miguel Soler, Sara Fortuna, 2016, izvirni znanstveni članek

Opis: Nanobodies (VHHs) have proved to be valuable substitutes of conventional antibodies for molecular recognition. Their small size represents a precious advantage for rational mutagenesis based on modelling. Here we address the problem of predicting how Camelidae nanobody sequences can tolerate mutations by developing a simulation protocol based on all-atom molecular dynamics and wholemolecule docking. The method was tested on two sets of nanobodies characterized experimentally for their biophysical features. One set contained point mutations introduced to humanize a wild type sequence, in the second the CDRs were swapped between single-domain frameworks with Camelidae and human hallmarks. The method resulted in accurate scoring approaches to predict experimental yields and enabled to identify the structural modifications induced by mutations. This work is a promising tool for the in silico development of single-domain antibodies and opens the opportunity to customize single functional domains of larger macromolecules
Najdeno v: osebi
Ključne besede: nanobodies, molecular dynamics, modeling, antibody solubility
Objavljeno: 11.10.2016; Ogledov: 2421; Prenosov: 181
.pdf Polno besedilo (1,95 MB)

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