Rücktitelbild: Hydrogen‐Bond Free Energy of Local Biological Water (Angew. Chem. 18/2020)

Ethyl-3-amino-2-benzoyl-2-butenoate crystallizes from pentane as either the E (mp 82–84 °C) or the Z-isomer (mp 95.5–96.5 °C). The E isomer is less stable, and changes spontaneously into the Z, which bas been identified by X-ray crystallography. The structure is characterised by an N–H/ester CO hydrogen bond and a very long C2—C3 bond (1.39 Å). Nuclear magnetic resonance methods have been used to measure the rate of [Formula: see text] isomerization at several temperatures, leading to the estimate that the free energy of activation at 268 K is 56 ± 8 kJ.

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Dynamic Properties of Water Confined in Graphene-Based Membrane: A Classical Molecular Dynamics Simulation Study

Membranes ◽

10.3390/membranes9120165 ◽

2019 ◽

Vol 9 (12) ◽

pp. 165 ◽

Cited By ~ 3

Author(s):

One-Sun Lee

Keyword(s):

Molecular Dynamics ◽

Hydrogen Bond ◽

Free Energy ◽

Graphene Sheets ◽

Water Molecules ◽

Energy Profile ◽

Confined Water ◽

Graphene Surface ◽

Dynamics Simulations ◽

Density Of Water

We performed molecular dynamics simulations of water molecules inside a hydrophobic membrane composed of stacked graphene sheets. By decreasing the density of water molecules inside the membrane, we observed that water molecules form a droplet through a hydrogen bond with each other in the hydrophobic environment that stacked graphene sheets create. We found that the water droplet translates as a whole body rather than a dissipate. The translational diffusion coefficient along the graphene surface increases as the number of water molecules in the droplet decreases, because the bigger water droplet has a stronger van der Waals interaction with the graphene surface that hampers the translational motion. We also observed a longer hydrogen bond lifetime as the density of water decreased, because the hydrophobic environment limits the libration motion of the water molecules. We also calculated the reorientational correlation time of the water molecules, and we found that the rotational motion of confined water inside the membrane is anisotropic and the reorientational correlation time of confined water is slower than that of bulk water. In addition, we employed steered molecular dynamics simulations for guiding the target molecule, and measured the free energy profile of water and ion penetration through the interstice between graphene sheets. The free energy profile of penetration revealed that the optimum interlayer distance for desalination is ~10 Å, where the minimum distance for water penetration is 7 Å. With a 7 Å interlayer distance between the graphene sheets, water molecules are stabilized inside the interlayer space because of the van der Waals interaction with the graphene sheets where sodium and chloride ions suffer from a 3–8 kcal/mol energy barrier for penetration. We believe that our simulation results would be a significant contribution for designing a new graphene-based membrane for desalination.

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Rational Computational Design of Fourth-Generation EGFR Inhibitors to Combat Drug-Resistant Non-Small Cell Lung Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms21239323 ◽

2020 ◽

Vol 21 (23) ◽

pp. 9323

Author(s):

Hwangseo Park ◽

Hoi-Yun Jung ◽

Kewon Kim ◽

Myojeong Kim ◽

Sungwoo Hong

Keyword(s):

Lung Cancer ◽

Hydrogen Bond ◽

Free Energy ◽

Small Cell ◽

Egfr Inhibitors ◽

Fourth Generation ◽

Wild Type ◽

Small Cell Lung ◽

Triple Mutant ◽

Exon 20

Although the inhibitors of singly mutated epidermal growth factor receptor (EGFR) kinase are effective for the treatment of non-small cell lung cancer (NSCLC), their clinical efficacy has been limited due to the emergence of various double and triple EGFR mutants with drug resistance. It has thus become urgent to identify potent and selective inhibitors of triple mutant EGFRs resistant to first-, second-, and third-generation EGFR inhibitors. Herein, we report the discovery of potent and highly selective inhibitors of EGFR exon 19 p.E746_A750del/EGFR exon 20 p.T790M/EGFR exon 20 p.C797S (d746-750/T790M/C797S) mutant, which were derived via two-track virtual screening and de novo design. This two-track approach was performed so as to maximize and minimize the inhibitory activity against the triple mutant and the wild type, respectively. Extensive chemical modifications of the initial hit compounds led to the identification of several low-nanomolar inhibitors of the d746-750/T790M/C797S mutant. Among them, two compounds exhibited more than 104-fold selectivity in the inhibition of EGFRd746-750/T790M/C797S over the wild type. The formations of a hydrogen bond with the mutated residue Ser797 and the van der Waals contact with the mutated residue Met790 were found to be a common feature in the interactions between EGFRd746-750/T790M/C797S and the fourth-generation inhibitors. Such an exceptionally high selectivity could also be attributed to the formation of the hydrophobic contact with a Gly loop residue or the hydrogen bond with Asp855 in the activation loop. The discovery of the potent and selective EGFRd746-750/T790M/C797S inhibitors were actually made possible by virtue of the modified protein–ligand binding free energy function involving a new hydration free energy term with enhanced accuracy. The fourth-generation EGFR inhibitors found in this work are anticipated to serve as a new starting point for the discovery of anti-NSCLC medicines to overcome the problematic drug resistance.

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On the Role of Hydrogen Bond Strength and Charge Transfer of a Diels-Alder Reaction On-Water: Semiempirical and Free Energy Calculations.

10.26434/chemrxiv.14399072.v1 ◽

2021 ◽

Author(s):

Andrés Henao Aristizàbal ◽

Yomna Gohar ◽

René Whilhelm ◽

Thomas D. Kühne

Keyword(s):

Hydrogen Bond ◽

Free Energy ◽

Charge Transfer ◽

Hydrogen Bonds ◽

Density Functional ◽

Alder Reaction ◽

Free Energy Calculations ◽

Diels Alder ◽

Diels Alder Reaction

Accelerated chemistry at the interface with water has received increasing attention. The mechanisms behind the enhanced reactivity On-Water are not yet clear. In this work we use a Langevin scheme in the spirit of second generation Car-Parrinello to accelerate the second-order density functional Tight-Binding (DFTB2) method in order to investigate the free energy of two Diels-Alder reaction On-Water: the cycloaddition between cyclopentadiene and ethyl cinnamate or thionocinnamate. The only difference between the reactants is the substitution of a carbonyl oxygen for a thiocarbonyl sulfur, making possible the distinction between them as strong and weak hydrogen-bond acceptors. We find a different mechanism for the reaction during the transition states and uncover the role of hydrogen bonds along with the reaction path. Our results suggest that acceleration of Diels-Alder reactions do not arise from an increased number of hydrogen bonds at the transition state and charge transfer plays a significant role. However, the presence of water and hydrogen-bonds is determinant for the catalysis of these reactions.

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Hydrogen Bond Stability of Quinazoline Derivatives Compounds in Complex against EGFR using Molecular Dynamics Simulation

Indonesian Journal of Chemistry ◽

10.22146/ijc.39567 ◽

2019 ◽

Vol 19 (2) ◽

pp. 461

Author(s):

Herlina Rasyid ◽

Bambang Purwono ◽

Thomas S Hofer ◽

Harno Dwi Pranowo

Keyword(s):

Molecular Dynamics ◽

Hydrogen Bond ◽

Free Energy ◽

Molecular Dynamics Simulation ◽

Binding Free Energy ◽

Dynamics Simulation ◽

Inhibition Mechanism ◽

Energy Calculation ◽

Protein Receptor ◽

The Stability

Lung cancer was a second common cancer case due to the high cigarette smoking activity both in men and women. One of protein receptor which plays an important role in the growth of the tumor is Epidermal Growth Factor Receptor (EGFR). EGFR protein is the most frequent protein mutation in cancer and promising target to inhibit the cancer growth. In this work, the stability of the hydrogen bond as the main interaction in the inhibition mechanism of cancer will be evaluated using molecular dynamics simulation. There were two compounds (A1 and A2) as new potential inhibitors that were complexed against the EGFR protein. The dynamic properties of each complexed were compared with respect to erlotinib against EGFR. The result revealed that both compounds had an interaction in the main catalytic area of protein receptor which is at methionine residue. Inhibitor A1 showed additional interactions during simulation time but the interactions tend to be weak. Inhibitor A2 displayed a more stable interaction. Following dynamics simulation, binding free energy calculation was performed by two scoring techniques MM/GB(PB)SA method and gave a good correlation with the stability of the complex. Furthermore, potential inhibitor A2 had a lower binding free energy as a direct consequence of the stability of hydrogen bond interaction.

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Mutagenic Distinction between the Receptor-Binding and Fusion Subunits of the SARS-CoV-2 Spike Glycoprotein and Its Upshot

Vaccines ◽

10.3390/vaccines9121509 ◽

2021 ◽

Vol 9 (12) ◽

pp. 1509

Author(s):

Robert Clark Penner

Keyword(s):

Hydrogen Bond ◽

Free Energy ◽

Receptor Binding ◽

General Principle ◽

Spike Glycoprotein ◽

Partial Explanation ◽

Subunit A ◽

Viral Glycoproteins ◽

Backbone Hydrogen Bond

We observe that a residue R of the spike glycoprotein of SARS-CoV-2 that has mutated in one or more of the current variants of concern or interest, or under monitoring, rarely participates in a backbone hydrogen bond if R lies in the S1 subunit and usually participates in one if R lies in the S2 subunit. A partial explanation for this based upon free energy is explored as a potentially general principle in the mutagenesis of viral glycoproteins. This observation could help target future vaccine cargos for the evolving coronavirus as well as more generally. A related study of the Delta and Omicron variants suggests that Delta was an energetically necessary intermediary in the evolution from Wuhan-Hu-1 to Omicron.

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