Deamidation reaction network mapping of pharmacologic and related proteins: impact of solvation dielectric on the degradation energetics of asparagine dipeptides

Abstract

Monoclonal antibodies (mAbs) are one of the most lucrative pharmacologics currently on the market due to their diverse array of applications. However, the diversity of these therapeutics is often limited...

Computing the Differences between Asn-X and Gln-X Deamidation and Their Impact on Pharmaceutical and Physiological Proteins: A Theoretical Investigation Using Model Dipeptides

“…Through prior studies, we had determined that the use of the B3LYP functional with the GD3 empirical dispersion correction was suitable for modeling our generated reaction networks. 28,59 Therefore, to maintain a self-consistent methodology through which the database of thermochemical and kinetic parameters associated with Gln-X deamidation could be analyzed against those generated for the Asn-X deamidation reaction network, we analyzed our modeled system under the same level of theory and chemical model as our prior studies. 28,59 Similar to the generation of the Asn-X deamidation reaction network, we modeled our reactions using a hybrid solvation model where one explicit water molecule acts as a passive stabilizer to our system.…”

“…28,59 Therefore, to maintain a self-consistent methodology through which the database of thermochemical and kinetic parameters associated with Gln-X deamidation could be analyzed against those generated for the Asn-X deamidation reaction network, we analyzed our modeled system under the same level of theory and chemical model as our prior studies. 28,59 Similar to the generation of the Asn-X deamidation reaction network, we modeled our reactions using a hybrid solvation model where one explicit water molecule acts as a passive stabilizer to our system. 28 The implicit component of our chemical model applies the CPCM implicit model to the modeled reaction.…”

“…28,59 Similar to the generation of the Asn-X deamidation reaction network, we modeled our reactions using a hybrid solvation model where one explicit water molecule acts as a passive stabilizer to our system. 28 The implicit component of our chemical model applies the CPCM implicit model to the modeled reaction. 28,60 The impact of the interactions between the different residue types and the solvated environment is reflected through the use of four different solvent dielectrics, ε = 4, 20, 40, and 80.…”

Toward Native Hardwood Lignin Pyrolysis: Insights into Reaction Energetics from Density Functional Theory

“…Details on the calculation of these properties, including the electronic, translational, rotational, and vibrational contributions for the molecular partition functions, can be found in the Supporting Information. Small inorganic systems with objectives of studying the reactive features similar to this work have been extensively studied with success in our group using comparable hybrid methodologies. − The radical product geometries were based on the geometry of the low energy conformation of the reactant, with the appropriate bonds cleaved, followed by optimization using the electronic structure methods previously described but without conformational searching. This approach has been used in previous works , to find the nearest local minimum while avoiding large-scale changes that could occur with a conformational search.…”

Systematic Mapping of Electrocatalytic Descriptors for Hybrid and Non-Hybrid Molybdenum Dichalcogenides with Graphene Support for Cathodic Hydrogen Generation

“…In the computational section of this work, atomistic modeling studies have been performed with periodic plane-wave density functional theory (DFT) to delve into the surface–electrochemistry of hydrogen binding (also known as chemisorption or adsorption). DFT study has become a powerful tool to provide critical insights into structural, electronic, optical, reactive, and energetic properties of materials and systems. − Binding energetics, which are considered major descriptors for catalytic performance but are difficult to attain with experimental measurement, have been calculated with DFT. The critical role of binding energy is stated by the Sabatier principle; that is, for ideal catalysis, the binding energy of key intermediates should be neither too strong nor too weak to ensure optimal catalysis. − In the case of HER, the well-established interpretation of the Sabatier principle is that for an optimal reaction rate, the binding free energy of hydrogen to the electrocatalyst surface should be zero. ,, In the computational part of this study, the conventional criterion of Δ G b ≈ 0 has been considered as the measure to establish the most suitable binding sites for HER catalysis.…”