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Abstract The metabolic product of caspase-1, IL-1β, is an important mediator in inflammation and pyroptosis cell death process. Alzheimer's disease, septic shock and rheumatoid arthritis are IL-1β mediated diseases, making the caspase-1 an interesting target of pharmacological value. Many inhibitors have been developed until now, most of them are peptidomimetic with improved potency. In the present study, all-atom molecular dynamics simulations and the MM/GBSA method were employed to reproduce and interpret the results obtained by in vitro experiments for a series of inhibitors. The analysis shows that the tautomeric state of the catalytic His237 impact significantly the performance of the prediction protocol, providing evidence for a His237 tautomeric state different to the proposed in the putative mechanism. Additionally, analysis of inhibitor-enzyme interactions indicates that the differences in the inhibitory potency of the tested ligands can be explained mainly by the interaction of the inhibitors with the S2–S4 protein region. These results provide guidelines for subsequent studies of caspase-1 catalytic reaction mechanism and for the design of novel inhibitors. Graphical abstract Image 1 Highlights • Binding energies of caspase-1 inhibitors depend on the protonation state of His237. • His237 is more likely found in its neutral form with the proton on the ε-nitrogen. • Our results suggest a revision of the putative caspase-1 reaction mechanism. • Interactions with His248, Glu 250, His342, Met345 residues are essential for inhibition. [ABSTRACT FROM AUTHOR]

Biological catalysis is a complex chemical process that involves not only electronic reorganization in the substrate but also the reorganization of the catalyst. This complexity is even larger in the case of post-transcriptional and post-translational modifications which may involve the interaction between two biomacromolecules. However, the development over the past decades of new computational methods and strategies is offering a detailed molecular picture of the catalytic event and a deep understanding of the mechanisms of chemical reactions in biological environments. Here we review the efforts made in the last years to model catalysis in post-transcriptional and post-translational processes. We stress on the advantages and problems of the different computational strategies and their applicability in different cases. [ABSTRACT FROM AUTHOR]

Abstract: Integrase (IN) is one of the three human immunodeficiency virus type 1 (HIV-1) enzymes essential for effective viral replication. S-1360 is a potent and selective inhibitor of HIV-1 IN. In this work, we have carried out molecular dynamics (MD) simulations using a hybrid Quantum Mechanics/Molecular Mechanics (QM/MM) approach, to determine the protein–ligand interaction energy for S-1360 and two analogues. Analysis of the MD trajectories reveals that the strongest protein–inhibitor interactions, observed in the three studied complexes, are established with Lys-159 residue and Mg2+ cation. Calculations of binding energy using BLYP/MM level of theory reveal that there is a direct relationship between this theoretical computed property and the experimental determined anti-HIV activity. [Copyright &y& Elsevier]

We report a theoretical study on the conformational equilibrium of chorismate that precedes its rearrangement to prephenate, an important enzyme-catalyzed reaction. In first place we show that the usual classification of chorismate conformers based on the relative position of the hydroxyl and ether bridge, pseudo-diaxial and pseudo-diequatorial, is not the only relevant factor from the point of view of the a posteriori rearrangement. Here we also analyse another complementary geometrical classification based on the interatomic distance between the carbon atoms to be bounded. Using the umbrella sampling approach and this distance as distinguished internal reaction coordinate, the gas phase AM1 and in solution AM1/TIP3P potentials of mean force (PMF) for the transformation between short- and long-distances and pseudo-diaxial and pseudo-diequatorial conformers have been calculated. This procedure has allowed a wide conformational structures analysis of chorismate. From the free energy minima and maximum of the profile obtained in gas phase as a function of the interatomic distance, we located stationary structures on the potential energy surface. Due to the fact that the use of this coordinate as distinguished reaction coordinate to get the PMF in solution presents important histeresis problems, the dihedral angle describing the position of the ether bridge with respect to the ring has also been used with successful results, both in gas phase and in solution. To carry out this study of the equilibrium between pseudo-diaxial and pseudo-diequatorial conformers, we have used another dihedral angle that describes the relative position of the two substituents of the ring: the ether bridge and the hydroxyl group. Our theoretical results predict a relative population of pseudo-diaxial and pseudo-diequatorial chorismate conformers in aqueous solution that are in very good agreement with experimental data reported in the literature. [Copyright &y& Elsevier]