Histidine hydrogen bonding in MHC at pH 5 and pH 7 modeled by molecular docking and molecular dynamics simulations

Hydrogen bonds play important roles in maintaining the structure of proteins and in the formation of most biomolecular protein-ligand complexes. All amino acids can act as hydrogen bond donors and acceptors. Among amino acids, Histidine is unique, as it can exist in neutral or positively charged forms within the physiological pH range of 5.0 to 7.0. Histidine can thus interact with other aromatic residues as well as forming hydrogen bonds with polar and charged residues. The ability of His to exchange a proton lies at the heart of many important functional biomolecular interactions, including immunological ones. By using molecular docking and molecular dynamics simulation, we examine the influence of His protonation/deprotonation on peptide binding affinity to MHC class II proteins from locus HLA-DP. Peptide-MHC interaction underlies the adaptive cellular immune response, upon which the next generation of commercially-important vaccines will depend. Consistent with experiment, we find that peptides containing protonated His residues bind better to HLA-DP proteins than those with unprotonated His. Enhanced binding at pH 5.0 is due, in part, to additional hydrogen bonds formed between peptide His+ and DP proteins. In acidic endosomes, protein His79β is predominantly protonated. As a result, the peptide binding cleft narrows in the vicinity of His79β, which stabilizes the peptide - HLA-DP protein complex. © 2014 Bentham Science Publishers.

Molecular architecture influences on material properties of pharmaceutical compounds

Salt formation has extensively been studied as a strategy to improve drug solubility but it has not been explored as a strategy to improve mechanical properties. A better understanding of which factors of the solid state can have an influence in the mechanical properties of pharmaceutical powders can help to optimise and reduce cost of tablet manufacturing. The aim of this study was to form different series of amine salts of flurbiprofen, gemfibrozil and diclofenac and to establish predictive relationships between architectural characteristics and physicochemical and mechanical properties of the salts. For this purpose, three different carboxylic acid drugs were selected: flurbiprofen, gemfibrozil and diclofenac, similar in size but varying in flexibility and shape and three different series of counterions were also chosen: one with increasing bulk and no hydroxyl groups to limit the hydrogen bonding potential; a second one with increasing number of hydroxyl groups and finally a third series, related to the latter in number of hydroxyl groups but with different molecular shape and flexibility. Physico-chemical characterization was performed (DSC, TGA, solubility, intrinsic dissolution rate, particle size, true density) and mechanical properties measured using a compaction replicator. Strained molecular conformations produce weaker compacts as they have higher energy than preferred conformations that usually lie close to energy minimums and oppose plastic deformation. It was observed that slip planes, which correspond to regions of weakest interaction between the planes, were associated with improved plasticity and stronger compacts. Apart from hydrogen bonds, profuse van der Waals forces can result in ineffective slip planes. Salts displaying two-dimensional densely hydrogen bonded layers produced stronger compacts than salts showing one-dimensional networks of non-bonded columns, probably by reducing the attachment energy between layers. When hydrogen bonds are created intramolecularly, it is possible that the mechanical properties are compromised as they do not contribute so much to create twodimensional densely bonded layers and they can force molecules into strained conformations. Some types of hydrogen bonding network may be associated with improved mechanical properties, such as type II, or R (10) 3 4 using graph-set notation, versus type III, or R (12) 4 8 , columns. This work clearly demonstrates the potential of investigating crystal structure-mechanical property relationship in pharmaceutical materials.

Evidence-based nanoscopic and molecular framework for excipient functionality in compressed orally disintegrating tablets

The work investigates the adhesive/cohesive molecular and physical interactions together with nanoscopic features of commonly used orally disintegrating tablet (ODT) excipients microcrystalline cellulose (MCC) and D-mannitol. This helps to elucidate the underlying physico-chemical and mechanical mechanisms responsible for powder densification and optimum product functionality. Atomic force microscopy (AFM) contact mode analysis was performed to measure nano-adhesion forces and surface energies between excipient-drug particles (6-10 different particles per each pair). Moreover, surface topography images (100 nm2-10 μm2) and roughness data were acquired from AFM tapping mode. AFM data were related to ODT macro/microscopic properties obtained from SEM, FTIR, XRD, thermal analysis using DSC and TGA, disintegration testing, Heckel and tabletability profiles. The study results showed a good association between the adhesive molecular and physical forces of paired particles and the resultant densification mechanisms responsible for mechanical strength of tablets. MCC micro roughness was 3 times that of D-mannitol which explains the high hardness of MCC ODTs due to mechanical interlocking. Hydrogen bonding between MCC particles could not be established from both AFM and FTIR solid state investigation. On the contrary, D-mannitol produced fragile ODTs due to fragmentation of surface crystallites during compression attained from its weak crystal structure. Furthermore, AFM analysis has shown the presence of extensive micro fibril structures inhabiting nano pores which further supports the use of MCC as a disintegrant. Overall, excipients (and model drugs) showed mechanistic behaviour on the nano/micro scale that could be related to the functionality of materials on the macro scale. © 2014 Al-khattawi et al.

Water network dynamics at the critical moment of a peptide's ß-turn formation:a molecular dynamics study

All-atom molecular dynamics simulations for a single molecule of Leu-Enkephalin in aqueous solution have been used to study the role of the water network during the formation of ß-turns. We give a detailed account of the intramolecular hydrogen bonding, the water-peptide hydrogen bonding, and the orientation and residence times of water molecules focusing on the short critical periods of transition to the stable ß-turns. These studies suggest that, when intramolecular hydrogen bonding between the first and fourth residue of the ß-turn is not present, the disruption of the water network and the establishment of water bridges constitute decisive factors in the formation and stability of the ß-turn. Finally, we provide possible explanations and mechanisms for the formations of different kinds of ß-turns.