The hydrophobic effect (HE) is commonly associated with the demixing of oil and water at ambient conditions and plays the leading role in determining the structure and stability of biomolecular assembly in aqueous solutions. On the molecular scale HE has an entropic origin. It is believed that hydrophobic particles induce order in the surrounding water by reducing the volume of configuration space available for hydrogen bonding. Here we show with computer simulation results that this traditional picture, based on average structural features of hydration water, configurational properties of single water molecules, and up to pairwise correlations, is not correct. Analyzing collective fluctuations in water clusters we are able to provide a fundamentally new picture of HE based on pronounced many-body correlations affecting the switching of hydrogen bonds (HBs) between molecules. These correlations emerge as a nonlocal compensation of reduced fluctuations of local electrostatic fields in the presence of an apolar solute. We propose an alternative view which may also be formulated as a maximization principle: The electrostatic noise acting on water molecules is maximized under the constraint that each water molecule on average maintains as many HBs as possible. In the presence of the solute the maximized electrostatic noise is a result of nonlocal fluctuations in the labile HB network giving rise to strong correlations among at least up to four water molecules.
COBISS.SI-ID: 5094426
A series of optimized sulfonamide derivatives was recently reported as novel inhibitors of UDP-N-acetylmuramoyl-L- alanine:D-glutamate ligase (MurD). These are based on naphthalene-N-sulfonyl-D-glutamic acid and have the D-glutamic acid replaced with rigidified mimetics. Here we have defined the binding site of these novel ligands to MurD using 1H/13C heteronuclear single quantum correlation. The MurD protein was selectively 13C-labeled on the methyl groups of Ile (d1 only), Leu and Val, and was isolated and purified. Crucial Ile, Leu and Val methyl groups in the vicinity of the ligand binding site were identified by comparison of chemical shift perturbation patterns among the ligands with various structural elements and known binding modes. The conformational and dynamic properties of the bound ligands and their binding interactions were examined using the transferred nuclear Overhauser effect and saturation transfer difference. In addition, the binding mode of these novel inhibitors was thoroughly examined using unrestrained molecular dynamics simulations. Our results reveal the complex dynamic behavior of ligand-MurD complexes and its influence on ligand-enzyme contacts. We further present important findings for the rational design of potent Mur ligase inhibitors.
COBISS.SI-ID: 5145882
One of the most difficult problems in chemistry is how a protein molecule folds from an unfolded state to its native conformation. It has been suggested that the local structural order (i.e., residual structure) may guide a polypeptide chain from the denatured to the native state. To understand the process of protein folding and misfolding, it is important to understand the nature of the local structural order in unfolded peptides and proteins. The local structural order in unfolded proteins is demonstrated by the following four indicators: the backbone conformational preferences, the nearest-neighbor effect, the cooperative formation of larger local structures, and the hydrophobic clusters. These indicators differ in the level of cooperativity, that is, the number of adjacent residues involved. The physical background of the local structural order in unfolded polypeptides is a highly controversial issue. In this review we show that solvation and electrostatic interactions can quantitatively explain the behavior of unfolded peptides and proteins
COBISS.SI-ID: 5044250
1H NMR Saturation Transfer Difference (STD) experiments were applied to study the binding of aspirin and of an anti-inflammatory complex of Cu(I), namely [Cu(tpp)(pmt)]2 [pmt = 2-mercaptopyrimidine), synthesized in an attempt to develop novel metallotherapeutic molecules. While aspirin showed only very weak binding, the complex [Cu(tpp)(pmt)]2 clearly favored binding to LOX-1. Insilico docking experiments in LOX-1 showed that aspirin does only weakly bind to LOX-1, while the complex binds with high affinity. In addition, docking experiments and molecular dynamics (MD) simulations showed that the complex binds via hydrogen bonding (HB), to an allosteric site of LOX-1, revealing that this enzyme has more than one accessible site for complex metallotherapeutic molecules. When aspirin was added in the solution containing LOX and the complex [Cu(tpp)(pmt)]2, the former was shown to hinder the binding of the Cu complex significantly. This may be interpreted as the copper complex aiding the transfer of aspirin through an acid-base reaction at the LOX enzyme which subsequently blocks its binding.
COBISS.SI-ID: 5123098
We have performed: (i) conformational analysis of two novel cytotoxic C2-substituted pyrrolo[2,3-f]quinolines 5e and 5g in deuterated dimethylsulfoxide (DMSO-d6) utilizing NOE results from NMR spectroscopy; (ii) molecular dynamics (MD) calculations in water, DMSO and dimyristoyl phosphatidylcholine bilayers and (iii) molecular docking and MD calculations on DNA nucleotide sequences. The obtained results for the two similar in structure molecules showed differences in: (i) their conformational properties in silico and in media that reasonably simulate the biological environment; (ii) the way they are incorporated into the lipid bilayers and therefore their diffusion ability and (iii) molecular docking capacity as it is depicted from their different binding scores.