A Scalable Molecular Force Field Parameterization Method Based on Density Functional Theory and Quantum-Level Machine Learning.

Fast and accurate molecular force field (FF) parameterization is still an unsolved problem. Accurate FF are not generally available for all molecules, like novel druglike molecules. While methods based on quantum mechanics (QM) exist to parameterize them with better accuracy, they are computationally expensive and slow, which limits applicability to a small number of molecules.

High-Throughput Automated Preparation and Simulation of Membrane Proteins with HTMD.

HTMD is a programmable scientific platform intended to facilitate simulation-based research in molecular systems. This paper presents the functionalities of HTMD for the preparation of a molecular dynamics simulation starting from PDB structures, building the system using well-known force fields, and applying standardized protocols for running the simulations. We demonstrate the framework's flexibility for high-throughput molecular simulations by applying a preparation, building, and simulation protocol with multiple force-fields on all of the seven hundred eukaryotic membrane proteins resolved to-date from the orientation of proteins in membranes (OPM) database.

Exploring O2 diffusion in A-type cytochrome c oxidases: molecular dynamics simulations uncover two alternative channels towards the binuclear site.

Cytochrome c oxidases (Ccoxs) are the terminal enzymes of the respiratory chain in mitochondria and most bacteria. These enzymes couple dioxygen (O2) reduction to the generation of a transmembrane electrochemical proton gradient. Despite decades of research and the availability of a large amount of structural and biochemical data available for the A-type Ccox family, little is known about the channel(s) used by O2 to travel from the solvent/membrane to the heme a3-CuB binuclear center (BNC).

The Pathway for O2 Diffusion inside CotA Laccase and Possible Implications on the Multicopper Oxidases Family.

Laccases and multicopper oxidases (MCOs) oxidize a wide range of organic compounds while reducing O2 to water, enabling numerous biotechnological applications. It is still unknown how O2 reaches the internalized catalytic center of MCOs where it gets reduced, despite a proposed channel inferred from X-ray crystallography structures. Herein, an alternative new pathway is found through the use of a combination of free energy calculations (implicit ligand sampling), landscape analysis, and Markov modeling.

Predicting the Thermodynamics and Kinetics of Helix Formation in a Cyclic Peptide Model.

The peptide Ac-(cyclo-2,6)-R[KAAAD]-NH2 (cyc-RKAAAD) is a short cyclic peptide known to adopt a remarkably stable single turn α-helix in water. Due to its simplicity and the availability of thermodynamic and kinetic experimental data, cyc-RKAAAD poses as an ideal model for evaluating the aptness of current molecular dynamics (MD) simulation methodologies to accurately sample conformations that reproduce experimentally observed properties. In this work, we extensively sample the conformational space of cyc-RKAAAD using microsecond-timescale MD simulations.

Putative dioxygen-binding sites and recognition of tigecycline and minocycline in the tetracycline-degrading monooxygenase TetX.

Expression of the aromatic hydroxylase TetX under aerobic conditions confers bacterial resistance against tetracycline antibiotics. Hydroxylation inactivates and degrades tetracyclines, preventing inhibition of the prokaryotic ribosome. X-ray crystal structure analyses of TetX in complex with the second-generation and third-generation tetracyclines minocycline and tigecycline at 2.

The role of Asp116 in the reductive cleavage of dioxygen to water in CotA laccase: assistance during the proton-transfer mechanism.

Multi-copper oxidases constitute a family of proteins that are capable of coupling the one-electron oxidation of four substrate equivalents to the four-electron reduction of dioxygen to two molecules of water. The main catalytic stages occurring during the process have already been identified, but several questions remain, including the nature of the protonation events that take place during the reductive cleavage of dioxygen to water. The presence of a structurally conserved acidic residue (Glu498 in CotA laccase from Bacillus subtilis) at the dioxygen-entrance channel has been reported to play a decisive role in the protonation mechanisms, channelling protons during the reduction process and stabilizing the site as a whole.

Structural consequences of ATP hydrolysis on the ABC transporter NBD dimer: molecular dynamics studies of HlyB.

ABC transporters are a large and important family of membrane proteins involved in substrate transport across the membrane. The transported substrates are quite diverse, ranging from monatomic ions to large biomolecules. Consequently, some ABC transporters are involved in biomedically relevant situations, from genetic diseases to multidrug resistance.

The multicopper oxidase from the archaeon Pyrobaculum aerophilum shows nitrous oxide reductase activity.

The multicopper oxidase from the hyperthermophilic archaeon Pyrobaculum aerophilum (McoP) was overproduced in Escherichia coli and purified to homogeneity. The enzyme consists of a single 49.6 kDa subunit, and the combined results of UV-visible, CD, EPR and resonance Raman spectroscopies showed the characteristic features of the multicopper oxidases.