ΔDFT/MIX:A reliable and efficient method for calculating core electron binding energies of large molecules

A new method, ΔDFT/MIX, is calibrated for use in calculating core electron binding energies. Chemically relevant test sets were used to determine the most accurate functionals out of the 70 density functionals included in GAMESS. The best three functionals, B3LYP, TPSSm, and BLYP, were used to calculate 1s electron binding energies of nucleic acid base tautomers, and the results were compared to experimental values to demonstrate accuracy and sensitivity of the method. Previously suggested methods such as ACD(4) and ΔMP2/MIX are as accurate as our new method; the overall mean absolute deviation of ΔDFT/MIX is 0.19 eV with B3LYP. Comparing calculation time shows that using DFT instead of MP2 is much less computationally costly for larger molecules

Computing UV–vis spectra of 1-bromo-1-propene: a comparison of model core potential and all-electron basis sets

Vacuum ultraviolet (VUV) spectroscopy can be used to identify different isomers in complicated mixtures of many molecules. In this work, calculated VUV spectra are compared with spectra of experimental mixtures to benchmark appropriate computational methods. Because the benchmark molecule, 1-bromo-1-propene, contains a heavy atom, both all-electron and model core potential basis sets were investigated. Time-dependent density functional theory (TD-DFT) can accurately compute electronic excited states at low-energy excitations and was cross-checked at higher energies against results from the symmetry adapted cluster–configuration interaction (SAC–CI) method. TD-DFT was determined to be satisfactory at low energies; however, excitation energies can deviate by 0.5 eV at high energies. TD-DFT with both all-electron and model core potential basis sets produced satisfactory excitation energies for the lower excited states. This method is also satisfactory at predicting spectra produced experimentally, including a mixture of isomers (cis- and trans-1-bromo-1-propene), with the exception of underestimating oscillator strength

Detailed Per-residue Energetic Analysis Explains the Driving Force for Microtubule Disassembly

<div><p>Microtubules are long filamentous hollow cylinders whose surfaces form lattice structures of <i>αβ</i>-tubulin heterodimers. They perform multiple physiological roles in eukaryotic cells and are targets for therapeutic interventions. In our study, we carried out all-atom molecular dynamics simulations for arbitrarily long microtubules that have either GDP or GTP molecules in the E-site of β-tubulin. A detailed energy balance of the MM/GBSA inter-dimer interaction energy per residue contributing to the overall lateral and longitudinal structural stability was performed. The obtained results identified the key residues and tubulin domains according to their energetic contributions. They also identified the molecular forces that drive microtubule disassembly. At the tip of the plus end of the microtubule, the uneven distribution of longitudinal interaction energies within a protofilament generates a torque that bends tubulin outwardly with respect to the cylinder's axis causing disassembly. In the presence of GTP, this torque is opposed by lateral interactions that prevent outward curling, thus stabilizing the whole microtubule. Once GTP hydrolysis reaches the tip of the microtubule (lateral cap), lateral interactions become much weaker, allowing tubulin dimers to bend outwards, causing disassembly. The role of magnesium in the process of outward curling has also been demonstrated. This study also showed that the microtubule seam is the most energetically labile inter-dimer interface and could serve as a trigger point for disassembly. Based on a detailed balance of the energetic contributions per amino acid residue in the microtubule, numerous other analyses could be performed to give additional insights into the properties of microtubule dynamic instability.</p></div

Computational Prediction and Experimental Validation of the Unique Molecular Mode of Action of Scoulerine

Scoulerine is a natural compound that is known to bind to tubulin and has anti-mitotic properties demonstrated in various cancer cells. Its molecular mode of action has not been precisely known. In this work, we perform computational prediction and experimental validation of the mode of action of scoulerine. Based on the existing data in the Protein Data Bank (PDB) and using homology modeling, we create human tubulin structures corresponding to both free tubulin dimers and tubulin in a microtubule. We then perform docking of the optimized structure of scoulerine and find the highest affinity binding sites located in both the free tubulin and in a microtubule. We conclude that binding in the vicinity of the colchicine binding site and near the laulimalide binding site are the most likely locations for scoulerine interacting with tubulin. Thermophoresis assays using scoulerine and tubulin in both free and polymerized form confirm these computational predictions. We conclude that scoulerine exhibits a unique property of a dual mode of action with both microtubule stabilization and tubulin polymerization inhibition, both of which have similar affinity values