This article reviews different formulations of the thermodynamic cycles used for the prediction of pK a values, their advantages, and disadvantages with special emphasis on the limitations resulting from the necessity of gas-phase calculations, which allow introducing some difficult cases that motivated alternative strategies. Before introducing the protocols that do not consider gas-phase calculations, the two current opinions available in the literature on the debate about the correct formalism for the calculation of free energies in solution are briefly introduced. Then, the isodesmic proton exchange reaction in solution is reviewed by analyzing its performance on difficult cases for thermodynamic cycles such as carbon acids and amino acids. The pK a values predicted by the isodesmic reaction for common acid species are also reviewed to compare their accuracy results in relation with those of thermodynamic cycles. Linear regressions between experimental pK a values and the calculated free energies obtained with the isodesmic reaction provide expressions for the dependence of the error in the calculated pK a s on the pK a difference between the studied acid and the reference species. Finally, it is shown that linear regressions correct the calculated free energies of the isodesmic reaction, when high constant precision is required in a large pK a range. The deviations from the expected behavior are equivalent to those reported previously for different pK a calculation protocols and are determined by the inaccuracies of continuum solvent models on the interactions with ionic species.

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Intrinsically disordered proteins (IDPs) are not well described by a single 3D conformation but by an ensemble of them, which makes their structural characterization especially challenging, both experimentally and computationally. Most all-atom force fields are designed for folded proteins and give too compact IDP conformations. α-Synuclein is a well-known IDP because of its relation to Parkinson’s disease (PD). To understand its role in this disease at the molecular level, an efficient methodology is needed for the generation of conformational ensembles that are consistent with its known properties (in particular, with its dimensions) and that is readily extensible to post-translationally modified forms of the protein, commonly found in PD patients. Herein, we have contributed to this goal by performing explicit-solvent, microsecond-long Replica Exchange with Solute Scaling (REST2) simulations of α-synuclein with the coarse-grained force field SIRAH, finding that a 30% increase in the default strength of protein–water interactions yields a much better reproduction of its radius of gyration. Other known properties of α-synuclein, such as chemical shifts, secondary structure content, and long-range contacts, are also reproduced. Furthermore, we have simulated a glycated form of α-synuclein to suggest the extensibility of the method to its post-translationally modified forms. The computationally efficient REST2 methodology in combination with coarse-grained representations will facilitate the simulations of this relevant IDP and its modified forms, enabling a better understanding of their roles in disease and potentially leading to efficient therapies.

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A Cd(ii) based 2D metal-organic framework (MOF), [Cd(4-bpd)(SCN)] (1) where 4-bpd = 1,4-bis(4-pyridyl)-2,3-diaza-1,3-butadiene, has been synthesized and characterized by standard methods including single crystal X-ray diffraction analysis. When it is sandwiched between ITO coated glass and Al, 1 shows interesting conduction properties. The I-V characteristics of the ITO/1/Al configuration measured in the dark and under illumination of incident light exhibit a highly non-linear rectifying behavior, which signifies its Schottky diode character. The conductivity of the configuration is 2.90 × 10 S m and 7.16 × 10 S m under dark and photoirradiation conditions, respectively. Different parameters have been analyzed and these indicate that 1 can be a promising candidate for light sensing electronic devices. This material has good sensitivity to the light source when switched on/off. Theoretical calculations have been performed to understand the reason for the enhancement of conductivity under illumination of incident light. It has been found that upon irradiation, slight changes in the bond distances of 4-bpd in 1 occur. These changes are related to the considerable decrease in the energy needed for the allowed electronic transition. This may influence the increase of conductivity along with other factors.

The origins of C-H activation in pyridoxal-5'-phosphate (PLP) Schiff bases and modulation of reaction specificity in PLP-enzymes are still not completely understood. There are no available studies that compare the reactivity of C4' carbons in ketimine Schiff bases with that of Cα carbons in their aldimine counterparts, which is essential to unravel the mechanisms that govern the evolution of their common carbanionic intermediates. Second-order rate constants for phosphate-catalyzed proton/deuterium exchange reactions in D(2)O of C4' carbons suffer a 10(5)-fold increase due to Schiff base formation (k(B) = 5.3 × 10(1) M(-1) s(-1)) according to NMR measurements. The C4' carbon acidity is also increased to pK(a) = 9.8, which is significantly higher than that of Cα in PLP-aldimines. DFT calculations reveal the role of each heteroatom in modulating the electrophilicity of C4' and Cα carbons. Specifically, the protonation state of pyridine nitrogen is the main factor in determining the absolute carbon acidity in aldimines (pK(a) of Cα varies from ∼14 to ∼23) and ketimines (pK(a) of C4' varies from ∼12 to ∼18), whereas the protonation state of both imine nitrogen and O3' phenol oxygen modulates the relative acidities of Cα and C4' from 1.5 to 7.5 pK(a) units. Our results provide an explanation to the modulation of reaction specificity observed in different PLP-enzymes based on the differences in the protonation state of the cofactor and H-bonding patterns in the active site.

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A comprehensive theoretical study based on density functional theory calculations (B3LYP and M06-2X functionals) of the formation of Schiff bases of pyridoxamine analogues with two different aldehydes was conducted. The reaction mechanism was found to involve two steps, namely: (1) formation of a carbinolamine and (2) dehydration of the carbinolamine to give the final imine. Also, consistent with available experimental evidence, the carbinolamine dehydration was the rate-determining step of the process determined by means of M06-2X functional. Using an appropriate solvation method and reactant conformation ensures that all proton transfers involved will be intramolecular, which substantially reduces energy barriers and facilitates reaction in all cases. The formation of a Schiff base between pyridoxal 5-phosphate (PLP) and an amine or amino acid requires the contribution of an external water molecule in order to facilitate proton transfers. On the other hand, the formation of a Schiff base between pyridoxamine 5-phosphate (PMP) and a carbonyl compound requires no external aid since the spatial arrangement of the functional groups in PMP ensures that all proton transfers will be intramolecular.