Protein-sol pKa: prediction of electrostatic frustration, with application to coronaviruses

Motivation Evolution couples differences in ambient pH to biological function through protonatable groups, in particular, those that switch from buried to exposed and alter protonation state in doing so. We present a tool focusing on structure-based discovery and display of these groups. Results Since prediction of buried group pKas is computationally intensive, solvent accessibility of ionizable groups is displayed, from which the user can iteratively select pKa calculation centers. Results are color-coded, with emphasis on buried groups. Utility is demonstrated with benchmarking against known pH sensing sites in influenza virus hemagglutinin and in variants of murine hepatitis virus, a coronavirus. A pair of histidine residues, which are conserved in coronavirus spike proteins, are predicted to be electrostatically frustrated at acidic pH in both pre- and post-fusion conformations. We suggest that an intermediate expanded conformation at endosomal pH could relax the frustration, allowing histidine protonation and facilitating conformational conversion of coronavirus spike protein. Availability and implementation This tool is available at http://www.protein-sol.manchester.ac.uk/pka/.

protein-sol pKa: prediction of electrostatic frustration, with application to coronaviruses

Evolution couples differences in ambient pH to biological function through protonatable groups, in particular those that switch from buried to exposed and alter protonation state in doing so. We present a tool focusing on structure-based discovery and display of these groups. Since prediction of buried group pKas is computationally intensive, solvent accessibility of ionisable groups is displayed, from which the user can iteratively select pKa calculation centers. Results are color-coded, with emphasis on buried groups. Utility is demonstrated with coronaviruses, which exhibit variable dependence on the acidic pH of the endocytotic pathway. After benchmarking with variants of murine hepatitis virus, a pair of conserved histidine residues are identified that are predicted to be electrostatically frustrated at acidic pH in a common structural core of pre- and post-fusion coronavirus spike proteins. We suggest that an intermediate expanded conformation at endosomal pH could relax the frustration, allowing histidine protonation, and facilitating conformational conversion. This tool is available at http://www.protein-sol.manchester.ac.uk/pka/.

A simple computational approach for pKa calculation of organosulfur compounds

The present work is related to predicting the pKa values of organosulfur compounds through Density Functional Theory (DFT). In this study 22 organo-sulfur compounds have been considered to calculate theoretical pKa values. Main emphasis has been given on the substitution of different groups on the Sulfur atom. The computations were performed in the presence of Dimethyl sulfoxide (DMSO) as solvent. Experimentally the order of increase of acidity is; Sulfides < < Sulfoxides < Sulfones. Our computed pKa values also follow the same order. The theoretical pKa values are computed using the DFT method B3LYP, with the basis sets 6-31G(d), 6-31+G(d,p) and IEFPCM bulk solvation model. The majority of computed pKa values are in excellent agreement with the experimental ones through the diffuse function basis set. Hence this computational approach, B3LYP/6-31+G(d,p)/IEFPCM, could be utilized to predict the pKa values of these types of organosulfur compounds.

An Ab Initio Investigation of the 4,4′-Methlylene Diphenyl Diamine (4,4′-MDA) Formation from the Reaction of Aniline with Formaldehyde

The most commonly applied industrial synthesis of 4,4′-methylene diphenyl diamine (4,4′-MDA), an important polyurethane intermediate, is the reaction of aniline and formaldehyde. Molecular understanding of the 4,4′-MDA formation can provide strategy to prevent from side reactions. In this work, a molecular mechanism consisted of eight consecutive, elementary reaction steps from anilines and formaldehyde to the formation of 4,4′-MDA in acidic media is proposed using accurate G3MP2B3 composite quantum chemical method. Then G3MP2B3-SMD results in aqueous and aniline solutions were compared to the gas phase mechanism. Based on the gas phase calculations standard enthalpy of formation, entropy and heat capacity values were evaluated using G3MP2B3 results for intermediates The proposed mechanism was critically evaluated and important side reactions are considered: the competition of formation of protonated p-aminobenzylaniline (PABAH+), protonated aminal (AMH+) and o-aminobenzylaniline (OABAH+). Competing reactions of the 4,4′-MDA formation is also thermodynamically analyzed such as the formation of 2,4-MDAH+, 3,4-MDAH+. AMH+ can be formed through loose transition state, but it becomes kinetic dead-end, while formation of significant amount of 2,4-MDA is plausible through low-lying transition state. The acid strength of the key intermediates such as N-methylenebenzeneanilium, PABAH+, 4-methylidenecyclohexa-2,5-diene-1-iminium, and AMH+ was estimated by relative pKa calculation.