The emergence of pandemic situations originated from severe acute respiratory syndrome (SARS)-CoV-2 and its new variants created worldwide medical emergencies. Due to the non-availability of efficient drugs and vaccines at these emergency hours, repurposing existing drugs can effectively treat patients critically infected by SARS-CoV-2. Finding a suitable repurposing drug with inhibitory efficacy to a host-protein is challenging. A detailed mechanistic understanding of the kinetics, (dis)association pathways, key protein residues facilitating the entry-exit of the drugs with targets are fundamental in selecting these repurposed drugs. Keeping this target as the goal of the paper, the potential repurposing drugs, Nafamostat, Camostat, Silmitasertib, Valproic acid, and Zotatifin with host-proteins HDAC2, CSK22, eIF4E2 are studied to elucidate energetics, kinetics, and dissociation pathways. From an ensemble of independent simulations, we observed the presence of single or multiple dissociation pathways with varying host-proteins-drug systems and quantitatively estimated the probability of unbinding through these specific pathways. We also explored the crucial gateway residues facilitating these dissociation mechanisms. Interestingly, the residues we obtained for HDAC2 and CSK22 are also involved in the catalytic activity. Our results demonstrate how these potential drugs interact with the host machinery and the specific target residues, showing involvement in the mechanism. Most of these drugs are in the preclinical phase, and some are already being used to treat severe COVID-19 patients. Hence, the mechanistic insight presented in this study is envisaged to support further findings of clinical studies and eventually develop efficient inhibitors to treat SARS-CoV-2.

The so-called 'iron maiden' molecules belong to one of the most interesting subgroups of cyclophanes due to the presence of the ultrashort interaction between the CX apical bond and the benzene ring. This article presents an in-depth theoretical study of 16 'iron maiden' molecules, in which X = H, F, Cl or Br and the side chains are of various lengths and types: CSC, CSCC, CCC, and CCCC. It is shown that the H → F → Cl → Br substitution leads to a significant expansion of the 'iron maiden' molecule. Shorter chains lead to more pronounced effects, while insertion of sulfur atoms into the side chains lowers them. Structural changes are associated with an increase in energetic destabilization of X. Moreover, unlike for H, in the case of X = halogen, the out → in isomerization is energetically disadvantageous. The 'iron maiden' molecules are characterized by the presence of only three X⋯CAr bond paths. Particularly noteworthy are unusually large (even up to 32) values of the X⋯CAr bond ellipticity, which results from flat electron density distribution. The X⋯π interaction in each of the investigated 'iron maiden' molecule turned out to be multi-center, stabilizing and almost purely covalent in nature as indicated by the definitely dominant percentage (94.8%-101.6%) of the exchange-correlation energy. The spatial hindrance within the 'iron maiden' molecules appears to be not so much due to the X⋯π repulsion, but due to unfavorable steric interactions between X and the CC side bonds. It is also confirmed that some CH⋯HC interactions in aliphatic chains can be very weakly stabilizing.

Polypeptoids differ from polypeptides in that the amide bond can more frequently adopt both cis and trans conformations. The transition between the two conformations requires overcoming a large energy barrier, making it difficult for conventional molecular simulations to adequately visit the cis and trans structures. A replica-exchange method is presented that allows for easy rotations of the amide bond and also an efficient linking to a high temperature replica. The method allows for just three replicas (one at the temperature and Hamiltonian of interest, a second high temperature replica with a biased dihedral potential, and a third connecting them) to overcome the amide bond sampling problem and also enhance sampling for other coordinates. The results indicate that for short peptoid oligomers, the conformations can range from all cis to all trans with an average cis/trans ratio that depends on side chain and potential model.

The density functional theory computational study indicates the possibility of the synthesis of seven-membered internal nitronates via cycloaddition reactions involving Z-C-aryl-N-methylnitrones and E-2-aryl-1-cyano-1-nitroethenes. The detailed exploration of the reaction paths indicates a polar, stepwise reaction mechanism through the zwitterionic intermediate. Using bonding evolution theory (BET), we have deciphered the molecular mechanism of the [4 + 3] cycloaddition reaction between E-2-phenyl-1-cyano-1-nitroethene and Z-C-phenyl-N-methylnitrone. The BET study has revealed that the formation of two CO single bonds takes place in the same way, through the depopulation of NC and CC bonding regions and monosynaptic basins, respectively. The first O1C7 single bond was formed in the sixth phase, while the second C3O4 bond was formed in the last ninth phase.

The 3D reference interaction site model (3D-RISM) of molecular solvation is a powerful tool for computing the equilibrium thermodynamics and density distributions of solvents, such as water and co-ions, around solute molecules. However, 3D-RISM solutions can be expensive to calculate, especially for proteins and other large molecules where calculating the potential energy between solute and solvent requires more than half the computation time. To address this problem, we have developed and implemented treecode summation for long-range interactions and analytically corrected cut-offs for short-range interactions to accelerate the potential energy and long-range asymptotics calculations in non-periodic 3D-RISM in the AmberTools molecular modeling suite. For the largest single protein considered in this work, tubulin, the total computation time was reduced by a factor of 4. In addition, parallel calculations with these new methods scale almost linearly and the iterative solver remains the largest impediment to parallel scaling. To demonstrate the utility of our approach for large systems, we used 3D-RISM to calculate the solvation thermodynamics and density distribution of 7-ring microtubule, consisting of 910 tubulin dimers, over 1.2 million atoms.

Machine learning methods have helped to advance wide range of scientific and technological field in recent years, including computational chemistry. As the chemical systems could become complex with high dimension, feature selection could be critical but challenging to develop reliable machine learning based prediction models, especially for proteins as bio-macromolecules. In this study, we applied sparse group lasso (SGL) method as a general feature selection method to develop classification model for an allosteric protein in different functional states. This results into a much improved model with comparable accuracy (Acc) and only 28 selected features comparing to 289 selected features from a previous study. The Acc achieves 91.50% with 1936 selected feature, which is far higher than that of baseline methods. In addition, grouping protein amino acids into secondary structures provides additional interpretability of the selected features. The selected features are verified as associated with key allosteric residues through comparison with both experimental and computational works about the model protein, and demonstrate the effectiveness and necessity of applying rigorous feature selection and evaluation methods on complex chemical systems.

Mechanistic details of cellulose depolymerization by non-thermal (atmospheric) plasma (NTAP) remains under-explored given the complexity of the medium. In this study, we have investigated the reaction mechanism of glycosidic-bond degradation triggered by reaction with hydroxyl radicals, considered as the principal reactive species in NTAP medium. In the first step of reaction sequence, H-abstraction reactions by HO‧ . radical on different CH sites of the pyranose ring were found to be non-selective and markedly exergonic giving rise to a set of cellobiosyl carboradicals likely to undergo further reactions. We then showed that cellobiosyl carboradicals are protected against direct hydrolysis, no activation of the (1-4)- β -glycosidic bond being characterized. Interestingly, a simple homolytic bond cleavage allowed to obtain desired monomer. Among the 18 possible fragmentations, involving CC and CO bond breaking from cellobiosyl carboradicals, 14 transition states were successfully identified, and only three reaction pathways proved kinetically and thermodynamically feasible. Natural bond orbital (NBO) analysis was performed to shed light on electronic structures of different compounds.

Fragment molecular orbital (FMO) method is a powerful computational tool for structure-based drug design, in which protein-ligand interactions can be described by the inter-fragment interaction energy (IFIE) and its pair interaction energy decomposition analysis (PIEDA). Here, we introduced a dynamically averaged (DA) FMO-based approach in which molecular dynamics simulations were used to generate multiple protein-ligand complex structures for FMO calculations. To assess this approach, we examined the correlation between the experimental binding free energies and DA-IFIEs of six CDK2 inhibitors whose net charges are zero. The correlation between the experimental binding free energies and snapshot IFIEs for X-ray crystal structures was R2  = 0.75. Using the DA-IFIEs, the correlation significantly improved to 0.99. When an additional CDK2 inhibitor with net charge of -1 was added, the DA FMO-based scheme with the dispersion energies still achieved R2  = 0.99, whereas R2 decreased to 0.32 employing all the energy terms of PIEDA.

In this work, we introduce an electrostatic and non-electrostatic (ENE) correction to the solvation energy based on the Solvent-Accessible Surface Area (SASA) of the solute and the solvent static dielectric constant. The proposed correction was developed for neutral solutes in non-aqueous solvents, considering three different implicit solvation models based on a Self-Consistent Reaction Field treatment of solute-solvent mutual polarization using an Apparent Surface Charge formalism, namely the Integral Equation Formalism of the Polarizable Continuum Model using a continuous surface charge scheme (PCM), the Solvation Model based on solute electron density (SMD), and the generalized Finite-Difference Poisson-Boltzmann (FDPB) model. The proposed correction was parametrized on a diverse training set of 4980 solvation data from the Solv@tum database of experimental solvation energies, and validated on the non-aqueous subset of the MNSOL database comprising 2140 solvation energies. The performances of the proposed ENE models with minimal and extended parameters formulations have been analyzed and the latter variant has been further compared to the widely used Cavity, Dispersion, and Solvent structural effects (CDS) non-electrostatic model originally developed for the SMx family of implicit solvation models. Overall, a very good agreement between the computed solvation energies with the ENE correction and the reference experimental data has been found on both the training and test sets for all continuum solvation models considered. Furthermore, results for the ENE correction are on par with the reference CDS non-electrostatic model for both SMD and FDPB electrostatics, but with the advantage of using a lower number of parameters and thus an improved transferability between different electrostatics treatments.

Per- and polyfluoroalkyl substances (PFAS) are robust "forever" chemicals that have become global environmental contaminants due to their inability to degrade using traditional techniques. In addition to the persistent nature of PFAS, the structural and functional diversity in PFAS creates a unique challenge in identification and remediation. Their identification is further complicated by the absence of standards for many PFAS. This work is aimed at developing a protocol for computing and establishing accurate 19 F NMR chemical shifts for PFAS using density functional theory (DFT), which can aid in the identification of PFAS. The impact of solvation and basis sets was evaluated by comparing the computed data with the experimental measurements. Results showed the addition of dispersion corrections in the methodology improve the accuracy of calculated NMR parameters within 4 ppm of the experimental values. Adding a second diffuse function and additional polarization did not improve the accuracy, likely because of the electronegativity of fluorine which does not allow the electron density of fluorine atoms to be polarized. The inclusion of various implicit solvation (DMSO, chloroform, and water) yielded negligible differences in accuracy, and were overall less accurate than the gas phase calculations. The most accurate methodology was then applied to more environmentally relevant PFAS, and the impact of helical nature on the NMR signatures was evaluated. The implication of this work is to be able to improve the identification of structurally diverse PFAS using the 19 F NMR.

Excitation energy transfer is a ubiquitous process of fundamental importance for understanding natural phenomena, such as photosynthesis, as well as advancing technologies ranging from photovoltaics to development of photosensitizers and fluorescent probes used to explore molecular interactions inside living cells. The current version of PyFREC 2.0 is an advancement of the previously reported software (D. Kosenkov, J. Comput. Chem. 2016, 37, 1847-1854). The current update is primarily focused on providing a computational tool based on Förster theory for bridging a gap between theoretically calculated molecular properties (e.g., electronic couplings, orientation factors, etc.) and experimentally measured emission and absorption spectra of molecules. The software is aimed to facilitate deeper understanding of photochemical mechanisms of fluorescence resonance energy transfer (FRET) in donor-acceptor pairs. Specific updates of the software include implementations of overlap integrals between donor emission and acceptor absorption spectra of FRET pairs, estimation of Strickler-Berg fluorescence lifetimes, calculation of Förster radii, energy transfer efficiency, and radiation zones that, in particular, determine applicability of the Förster theory.

p-Phenylenediamine (p-PDA) is a monomer of many important polymers such as kevlar, twaron, poly-p-PDA. Most of the noticed polymers formation is initiated by a free-radical, but their polymerization mechanism is not elucidated computationally. The proposed study helps to fully understand the frequently utilized initiator/oxidant, potassium persulfate (K2 S2 O8 ) role in the aromatic diamines polymerization, which support experimental protocols, and a polymer scope. The formation of the poly-p-PDA is studied with the density functional theory (DFT) B3LYP-D3 functional using experimental polymerization parameters (0°C and aqueous media). K2 S2 O8 initiated free-radical polymerization of p-PDA is studied in detail, taking into account sulfate free-radical (SO4 - )· , SFR, persulfate anion (S2 O8 )2- , PA and K2 S2 O8 cluster, PP. The reaction mechanism is calculated as the conversion of p-PDA to free-radical, the p-PDA free-radical attack to the next p-PDA (dimerization), ammonia extrusion from the dimer adduct, the dimer adduct conversion to the free-radical (completion of p-PDA polymerization cycle) for the polymer chain elongation. Calculations show that the dimerization step is the rate-limiting step with a 29.2 kcal/mol energy barrier when SFR initiates polymerization. In contrast, the PA-assisted dimerization energy barrier is only 12.7 kcal/mol. PP supported polymerization is calculated to have very shallow energy barriers completing the polymerization cycle, i.e., dimerization (TS2K, ∆G‡  = 11.6 kcal/mol) and ammonia extrusion (TS3K, ∆G‡  = 6.7 kcal/mol).

By means of density functional theory calculations, the encapsulation capabilities of a series of azobenzen-containing photoresponsive nanoring hosts (labeled as host 1, 2, 3, 4, 5 and 6 according to the number of the azo unit, respectively) for fullerene C60 were surveyed. Interestingly and abnormally, it is found that the host 5, of which the diameter is only 1.218 nm, can form stable full inclusion complex with C60 . However, irrespective of their cavity sizes (11.98 ~ 12.94 Å) of the hosts, the structures 1 ~ 4 and 6 were all disable to form inclusion complex with C60 . In this paper, the group-number-composition-selective full inclusion host-guest interaction of the azobenzene-containing nanorings with fullerene C60 is firstly presented. The calculated interaction energies, together with the detection and visualization of the weak interaction regions, provided evidences for the host-guest binding based on relative strong repulsion interaction in the full inclusion complex. Analysis on the frontier orbital feature of the host-guest systems suggests that under the electron excited condition, the chemical activity may be transferred from host 5 to guest C60 by formation of the floating host-guest complex, and the chemical reactivity of the host 5 can be passivated via formation of the full inclusion host-guest complex. Additionally, UV-vis-NIR and 1 H NMR spectra of the hosts before and after the formations of the complexes have been simulated and discussed qualitatively, which may be helpful for further experimental investigations in future.

The chemistry of divalent lanthanides, Ln2+ , is a growing sub-field of heavy element chemistry owing to new synthetic approaches. However, some theoretical aspects of these unusual cations are currently underdeveloped, especially as they relate to their dynamic properties in solution. In this work, we address the hydration of two of the classical Ln2+ cations, Sm2+ and Eu2+ , using atomic multipole optimized energetic for biomolecular applications (AMOEBA) force fields. These cations have not been parameterized to date with AMOEBA, and few studies are available because of their instability with respect to oxidation in aqueous media. Coordination numbers (CN's) of 8.2 and 8.1 respectively for Sm2+ and Eu2+ , and 8.8 for both Sm3+ and Eu3+ have been obtained and are in good agreement with the few available AIMD and X-ray absorption fine structures studies. The decreased CN of Ln2+ compared with Ln3+ arises from progressive water exchange events that indicates the gradual stabilization of 8-coordinate structures with respect to 9-coordinate geometries. Moreover, the effects of the chloride counter anions on the coordination of Ln2+ cations have been studied at different chloride concentrations in this work. Lastly, water exchange times of Ln2+ cations have been calculated to provide a comprehensive understanding of the behavior of Eu2+ and Sm2+ in aqueous chloride media.

We report here for the first time the potential energy surfaces (PES) of phenyletilamine (PEA) and meta-tyramine (m-OH-PEA) at the D2 dopamine receptor (D2DR) binding site. PESs not only allow us to observe all the critical points of the surface (minimums, maximums, and transition states), but also to note the ease or difficulty that each local minima have for their conformational inter-conversions and therefore know the conformational flexibility that these ligands have in their active sites. Taking advantage of possessing this valuable information, we analyze how accurate a standard docking study is in these cases. Our results indicate that although we have to be careful in how to carry out this type of study and to consider performing some extra-simulations, docking calculations can be satisfactory. In order to analyze in detail the different molecular interactions that are stabilizing the different ligand-receptor (L-R) complexes, we carried out quantum theory of atoms in molecules (QTAIM) computations and NMR shielding calculations. Although some of these techniques are a bit tedious and require more computational time, our results demonstrate the importance of performing computational simulations using different types of combined techniques (docking/MD/hybrid QM-MM/QTAIM and NMR shielding calculations) in order to obtain more accurate results. Our results allow us to understand in details the molecular interactions stabilizing and destabilizing the different L-R complexes reported here. Thus, the different activities observed for dopamine (DA), m-OH-PEA, and PEA can be clearly explained at molecular level.