Journal of Theoretical and Computational Chemistry最新文献

Empirical force field methods typically rely on point charges to describe the electrostatic interactions, which is problematic when anisotropy needs to be considered, as in the case of the electrostatic potential of covalently bound halogens that possess a positive site, termed $\sigma$-hole, surrounded by a large negative belt. To address this, an off-center point charge (extra point, EP) is usually placed at a given distance from the halogen to emulate the $\sigma$-hole and commonly used implementations are based on the restrained electrostatic potential (RESP) procedure to fit atomic charges, being one of the most used charge models. In this context, no specific Merz–Singh–Kollman (MK) radius for iodine is available in the literature, which is an essential parameter in the RESP fitting procedure. In this work, we explored the impact of the iodine MK radius on the obtained RESP charges for a set of 12 iodinated molecules. We verified that the relative root mean square (RRMS) values obtained with and without an EP kept decreasing with increasing radii for most compounds, thus impairing optimization using such a procedure. Nevertheless, the use of an iodine MK radius lower than 2 Å is not advisable since the RRMS kept decreasing considerably until this value was reached. Moreover, the performance of three iodine MK radii was studied with the estimation of the free energy of hydration ($\mathrm{\Delta }{G}_{\mathrm{hyd}}$) values using alchemical free energy calculations, which are particularly sensitive to the charges used. Despite the usage of different radii not leading to remarkable differences, our results indicate that using a value of 2.70 Å leads to lower mean absolute errors (MAE) and root mean squared error (RMSE) values when comparing the calculated with the experimental $\mathrm{\Delta }{G}_{\mathrm{hyd}}$ values.

The S_N2 and proton transfer (PT) pathways for ${\mathrm{\text{OH}}}^{-}+{\mathrm{\text{NH}}}_2$Cl reaction are represented by employing various electronic structure computations. Both back-side S_N2 and PT channels are exothermic and stationary points of PESs are below the reactant asymptote. Overall, the PES is similar to the C-centered S_N2 reactions. Conversely, ion-dipole complex was not found for ${\mathrm{\text{OH}}}^{-}+{\mathrm{\text{NH}}}_2$Cl system. The N–HOH/NH–Cl hydrogen bond characterizes on either side of the reaction barrier of nitrogen complexes. Moreover, a halogen-bonded complex (HO⁻–ClNH₂) and two types of H-bond complexes (HONH₂–Cl⁻ and Cl⁻–HONH₂) were described, predicting an important role in dynamics. The PT pathway may be the major channel in the title system, which is contradictory to ${\mathrm{\text{OH}}}^{-}+{\mathrm{\text{CH}}}_3$Cl and ${\mathrm{\text{F}}}^{-}+{\mathrm{\text{NH}}}_2$Cl reactions. Here, MP2, B3LYP and CAM-B3LYP methods show overall excellent consistency with CCSD(T)/CBS energies and are recommended to carry out dynamics simulations.

Bone morphogenetic proteins (BMPs) are multi-functional growth factors that initiate, promote and maintain cartilage and bone morphogenesis, differentiation and regeneration in both the developing embryo and adult. The proteins have a conformational wrist epitope and a linear knuckle epitope responsible for, respectively, type-I and type-II receptor binding, as well as a hybrid armpit epitope targeted by natural BMP antagonists. In this study, the recognition and interaction between human BMPs and their pan-antagonist Crossveinless was investigated systematically at molecular level. It is revealed that the armpit epitope shares a roughly common region over different BMPs, which consists of a loop segment and a turn segment that are sequentially discontinuous but spatially vicinal on these BMP protein surfaces. Turn segment is the primary binding site that can be bound effectively by Crossveinless using a tightly packed mode. The segment was further extended at its two termini to cover a complete double-stranded sheet of BMPs, which was then split from the interfacial context of BMP–Crossveinless complexes to derive a series of osteogenic peptides; they exhibit moderate intrinsic disorder in free state, but can be constrained into a native-like conformation by stapling a disulfide bridge across two strands of the sheet. The disulfide bridge was rationally designed and optimized to avoid disrupting the native interaction of BMP sheet peptides with the active pocket of Crossveinless. Biophysical assays substantiated that the binding affinities of resulting cyclic peptides were improved by 2–6-fold relative to their linear counterpart upon the stapling, in which the cyclic peptide Bmp7-sb1 (S[CLYFDDNSNVILC]K) derived from the double-stranded sheet region of BMP7 armpit epitope was determined to have the highest affinity to Crossveinless in all tested samples. These rationally designed epitope-derived peptides can be used as osteogenic agents to activate the human BMP signaling by competitively targeting their natural antagonist.