1,721,045 research outputs found
Molecular modelling of the affinity chromatography of proteins: Status and perspectives
No full textAffinity chromatography is among the most widely used methodologies for the purification of proteins. Despite of this, a molecular understanding of its working principles is essentially still missing, mostly because of the difficulty of disentangling the contribution of the different components responsible for the affinity interaction. Molecular modelling, which has greatly progressed in the last years, offers a chance to improve greatly our understanding of this complex process. In this perspective it will be discussed how this is possible and what are the most likely rewards from this effort. Several examples of recent progress in the field will be given as well as a list of open problems and challenges
Molecular modeling to rationalize ligand-support interactions in affinity chromatography
No full textFirst principles assessment of solvent induced cage effects on intramolecular hydrogen transfer in the free radical polymerization of acrylates
Full text linkWe investigate the rate constant of poly-butyl acrylate backbiting between 310 and 510 K using semi-empirical metadynamics in the gas phase, bulk and solution. The simulations in the condensed phase are performed through a hybrid quantum mechanics/molecular mechanics approach. The free energy landscape associated with the reactive events under vacuum and in the condensed phase is used to correct harmonic transition state theory (TST) rate constants. The Arrhenius parameters so determined are introduced in a semi-detailed mechanistic kinetic mechanism of butyl acrylate polymerization in bulk and in solution, allowing it to test how the butyl acrylate polymerization rate is affected by solvent-induced cage effects on backbiting. The results show that the backbiting rate constant is higher in the condensed phase than in the gas phase. In addition, a twofold increase is observed in xylene compared to the bulk. These results differ significantly from previous theoretical calculations, especially at high temperatures, aligning better with experimental rate measurements. The semi-detailed model, incorporating our calculated rate coefficients, is validated against monomer concentration profiles from bulk and solution polymerizations in various reactor configurations, demonstrating good agreement with experimental data. This study paves the way for developing detailed kinetic models in the condensed phase using a priori kinetic parameters derived from molecular simulations, thus widening their range of applicability beyond the one experimentally accessible
Kinetics of protein-ligand unbinding: Predicting pathways, rates, and rate-limiting steps
No full textThe ability to predict the mechanisms and the associated rate constants of protein-ligand unbinding is of great practical importance in drug design. In this work we demonstrate how a recently introduced metadynamics-based approach allows exploration of the unbinding pathways, estimation of the rates, and determination of the rate-limiting steps in the paradigmatic case of the trypsin-benzamidine system. Protein, ligand, and solvent are described with full atomic resolution. Using metadynamics, multiple unbinding trajectories that start with the ligand in the crystallographic binding pose and end with the ligand in the fully solvated state are generated. The unbinding rate k off is computed from the mean residence time of the ligand. Using our previously computed binding affinity we also obtain the binding rate k on. Both rates are in agreement with reported experimental values. We uncover the complex pathways of unbinding trajectories and describe the critical rate-limiting steps with unprecedented detail. Our findings illuminate the role played by the coupling between subtle protein backbone fluctuations and the solvation by water molecules that enter the binding pocket and assist in the breaking of the shielded hydrogen bonds. We expect our approach to be useful in calculating rates for general protein-ligand systems and a valid support for drug design
Unveiling Solvent Effects on β-Scissions through Metadynamics and Mean Force Integration
No full textThis study introduces a methodology that combines accelerated molecular dynamics and mean force integration to investigate solvent effects on chemical reaction kinetics. The newly developed methodology is applied to the β-scission of butyl acrylate (BA) dimer in polar (water) and nonpolar (xylene and BA monomer) solvents. The results show that solvation in both polar and nonpolar environments reduces the free energy barrier of activation by ∼4 kcal/mol and decreases the pre-exponential factor 2-fold. Employing a hybrid quantum mechanics/molecular mechanics approach with explicit solvent modeling, we compute kinetic rate constants that better match experimental measurements compared to previous gas-phase calculations. This methodology presents promising potential for accurately predicting kinetic rate constants in liquid-phase polymerization and depolymerization processes
Determination of Energies and Sites of Binding of PFOA and PFOS to Human Serum Albumin
No full textStructure and energies of the binding sites of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) to human serum albumin (HSA) were determined through molecular modeling. The calculations consisted of a compound approach based on docking, followed by molecular dynamics simulations and by the estimation of the free binding energies adopting WHAM-umbrella sampling and semiempirical methodologies. The binding sites so determined are common either to known HSA fatty acids sites or to other HSA sites known to bind to pharmaceutical compounds such as warfarin, thyroxine, indole, and benzodiazepin. Among the PFOA binding sites, five have interaction energies in excess of -6 kcal/mol, which become nine for PFOS. The calculated binding free energy of PFOA to the Trp 214 binding site is the highest among the PFOA complexes, -8.0 kcal/mol, in good agreement with literature experimental data. The PFOS binding site with the highest energy, -8.8 kcal/mol, is located near the Trp 214 binding site, thus partially affecting its activity. The maximum number of ligands that can be bound to HSA is 9 for PFOA and 11 for PFOS. The calculated data were adopted to predict the level of complexation of HSA as a function of the concentration of PFOA and PFOS found in human blood for different levels of exposition. The analysis of the factors contributing to the complex binding energy permitted to outline a set of guidelines for the rational design of alternative fluorinated surfactants with a lower bioaccumulation potential
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