Simple Physics-Based Analytical Formulas for the Potentials of Mean Force of the Interaction of Amino Acid Side Chains in Water. VII. Charged–Hydrophobic/Polar and Polar–Hydrophobic/Polar Side Chains

The physics-based potentials of side-chain–side-chain interactions corresponding to pairs composed of charged and polar, polar and polar, charged and hydrophobic, and hydrophobic and hydrophobic side chains have been determined. A total of 144 four-dimensional potentials of mean force (PMFs) of all possible pairs of molecules modeling these pairs were determined by umbrella-sampling molecular dynamics simulations in explicit water as functions of distance and orientation, and the analytical expressions were then fitted to the PMFs. Depending on the type of interacting sites, the analytical approximation to the PMF is a sum of terms corresponding to van der Waals interactions and cavity-creation involving the nonpolar sections of the side chains and van der Waals, cavity-creation, and electrostatic (charge–dipole or dipole–dipole) interaction energies and polarization energies involving the charged or polar sections of the side chains. The model used in this work reproduces all features of the interacting pairs. The UNited RESidue force field with the new side-chain–side-chain interaction potentials was preliminarily tested with the N-terminal part of the B-domain of staphylococcal protein A (PDBL 1BDD; a three-α-helix bundle) and UPF0291 protein YnzC from Bacillus subtilis (PDB: 2HEP; an α-helical hairpin)

Toward Temperature-Dependent Coarse-Grained Potentials of Side-Chain Interactions for Protein Folding Simulations. II. Molecular Dynamics Study of Pairs of Different Types of Interactions in Water at Various Temperatures

By means of molecular dynamics simulations of 15 pairs of molecules selected to model the interactions of nonpolar, nonpolar and polar, nonpolar and charged, polar, and polar and charged side chains in water, we determined the potentials of mean force (PMFs) of pairs of interacting molecules in water as functions of distance between the interacting particles or their distance and orientations at three temperatures: 283, 323, and 373 K, respectively. The systems were found to fall into the following four categories as far as the temperature dependence of the PMF is concerned: (i) pairs for which association is entropy-driven, (ii) pairs for which association is energy-driven, (iii) pairs of positively charged solute molecules, for which association is energy-driven with unfavorable entropy change, and (iv) the remaining systems for which temperature dependence is weak. For each pair of PMFs, entropic and energetic contributions have been discussed

Can Nitriles Be Stronger Bases Than Proton Sponges in the Gas Phase? A Computational Analysis

DFT calculations have been performed for a series of push–pull nitriles [(R₂N)_<i>n</i>(XY)_<i>i</i>CN, where <i>i</i> = 0, 1, or 2, <i>n</i> = 1, 2, or 3, R₂N = H₂N, Me₂N, or C₄H₈N, X = CH, N, or P, Y = CH or N]. The possible protonation <i>N</i>-sites (<i>N</i>-cyano, <i>N</i>-imino, and <i>N</i>-amino) have been examined and their proton affinities (PA) estimated. For all compounds in the series, even for those containing the guanidino, phosphazeno, and diphosphazeno pushing groups, the <i>N</i>-cyano atom is the favored site of protonation. The n−π conjugation strongly decreases the PA value of the pushing amino group in favor of the pulling cyano one. Nitriles with the phosphazeno groups [(R₂N)₃PNP­(R₂N)₂N and (R₂N)₃PN] exhibit the strongest basicity in the series. Some of them (with PA > 1000 kJ mol^–1) are stronger bases than DMAN, the so-called “proton sponge”. Nitriles bearing the guanidino group [(R₂N)₂CN] are less basic than those with the phosphazeno group [(R₂N)₃PN] but more basic than those with the formamidino group (R₂NCHN) containing the same substituent R. The <i>N</i>-imino atoms, present in the transmitter group (XN, X = CH, N, or P), display PA values lower than those of the <i>N</i>-cyano site by more than 30 kJ mol^–1. When proceeding from the unsubstituted derivatives (R = H) to the methylated ones (R = Me), the Me groups at the <i>N</i>-amino atom increase the PA value of the <i>N</i>-cyano site for Me₂NXYCN (X, Y = CH or N) by <i>ca</i>. 30–60 kJ mol^–1. For the guanidino and phosphazeno derivatives containing two and three amino groups, respectively, this effect is not additive. The four Me groups for (Me₂N)₂CNCN and the six Me groups for (Me₂N)₃PNCN increase the PA­(<i>N</i>-cyano) values by only 30–50 kJ mol^–1. The CN bond lengths of the neutral forms are well correlated with the PA­(<i>N</i>-cyano) values

Theoretical Studies of Interactions between O‑Phosphorylated and Standard Amino-Acid Side-Chain Models in Water

Phosphorylation is a common post-translational modification of the amino-acid side chains (serine, tyrosine, and threonine) that contain hydroxyl groups. The transfer of the negatively charged phosphate group from an ATP molecule to such amino-acid side chains leads to changes in the local conformations of proteins and the pattern of interactions with other amino-acid side-chains. A convenient characteristic of the side chain–side chain interactions in the context of an aqueous environment is the potential of mean force (PMF) in water. A series of umbrella-sampling molecular dynamic (MD) simulations with the AMBER force field were carried out for pairs of O-phosphorylated serine (pSer), threonine (pThr), and tyrosine, (pTyr) with natural amino acids in a TIP3P water model as a solvent at 298 K. The weighted-histogram analysis method was used to calculate the four-dimensional potentials of mean force. The results demonstrate that the positions and depths of the contact minima and the positions and heights of the desolvation maxima, including their dependence on the relative orientation depend on the character of the interacting pairs. More distinct minima are observed for oppositely charged pairs such as, e.g., O-phosphorylated side-chains and positively charged ones, such as the side-chains of lysine and arginine

Quantum-Chemical Studies on the Favored and Rare Tautomers of Neutral and Redox Adenine

All possible twenty-three prototropic tautomers of neutral and redox adenine (nine amine and fourteen imine forms, including geometric isomerism of the exo NH group) were examined in vacuo {DFT­(B3LYP)/6-311+G­(d,p)}. The NH → NH conversions as well as those usually omitted, NH → CH and CH → CH, were considered. An interesting change of the tautomeric preference occurs when proceeding from neutral to reduced adenine. One-electron reduction favors the nonaromatic amine C8H–N10H tautomer. This tautomeric preference is similar to that (C2H) for reduced imidazole. Water molecules (PCM model) seem to not change this trend. They influence solely the relative energies. The DFT vertical detachment energy in the gas phase is positive for each tautomer, e.g., 0.03 eV for N9H–N10H and 1.84 eV for C8H–N10H. The DFT adiabatic electron affinity for the favored process, neutral N9H–N10H → reduced C8H–N10H (ground states), is equal to 0.18 eV at 0 K (ZPE included). One-electron oxidation does not change the tautomeric preference in the gas phase. The aromatic amine N9H–N10H tautomer is favored for the oxidized molecule similarly as for the neutral one. The DFT adiabatic ionization potential for the favored process, neutral N9H–N10H → oxidized N9H–N10H (ground states), is equal to 8.12 eV at 0 K (ZPE included). Water molecules (PCM model) seem to influence solely the composition of the tautomeric mixture and the relative energies. They change the energies of the oxidation and reduction processes by ca. 2 eV