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The propensity to form fibril in disease-related proteins is a widely studied phenomenon, but its correlation, if any, with structural characteristics of the associated proteins is not clearly understood. However, the observation has been made that some proteins that readily form amyloid have a significant number of backbone H bonds that are exposed to solvent molecules, suggesting that these regions have a propensity toward protein interaction and aggregation [Fernandez, A. & Scheraga, H. A. (2003) Proc. Natl. Acad. Sci. USA 100, 113-118]. High-resolution x-ray structures of the sheep and human C-terminal prion protein have provided a useful description of surface and partially buried waters. By molecular dynamics simulations, we investigated the structural role of these water molecules. The solvent dynamical behavior on the protein surface reveals significant features about the stability and the potential interactions of the prion protein. The protein presents regions of tightly bound conserved waters that are necessary to hold in place local elements of the fold, as well as regions where the local water is in fast exchange with bulk water. These results are evidenced by a map of the spatial distribution entropy of the solvent around the protein. The particular behavior of the solvent around these regions may be crucial in the folding stability and in terms of aggregation loci. molecular dynamics | prion protein | PrP Q217R mutation | solvent entropy | protein solvation

Structural and charge interaction analyses of the binding site of the aspartate 95 mutants of the Desulfovibrio vulgaris flavodoxin reveals the role played by the hydrogen bonding in the modulation of the redox potentials of the bound flavodoxin, particularly the carboxylate group of the mutant.

Researchers describe the structural changes that occur as the lipase from Thermomyces lanuginosa is activated in the presence of lipids. During this process the enzyme exists in a low activity form, an activated form, and a fully active form.

The dynamics of the enzyme ribonuclease-Sa as a function of temperature is explored through a series of molecular dynamics simulations. The enzyme is preorganized dynamically, regions with low plasticity confer specificity while the more flexible regions have the fluidity to facilitate energetically inexpensive conformational rearrangements such as those required to achieve the transition state.

The rotation of a water molecule buried inside a protein bovine pancreatic trypsin inhibitor (BPTI) was examined. Reaction path calculations using conjugate peak refinement were employed to compute the transition state and activation energy for the rotation in both BPTI and ice. The behavior of the structural water, which results to the interchange of two water hydrogens, was found to be similar in both ice and BPTI. The complex process involves two successive rotations around the orthogonal axes.

Water deeply buried in proteins is considered to be an integral part of the folded structure. Such structural water molecules make strong H bonds with polar groups of the surrounding protein and therefore are believed to tighten the protein matrix. Surprisingly, our computational analysis of the binding of a buried water molecule to bovine pancreatic trypsin inhibitor shows that the protein actually becomes more flexible, as revealed by an increase in the vibrational entropy. We find that this effect must be common in proteins, because the large entropic cost of immobilizing a single water molecule [-T[Delta]S = 20.6 kcal/mol (1 kcal = 4.18 kJ) for the lost translational and rotational degrees of freedom] can only be partly compensated by water-protein interactions, even when they are nearly perfect, as in the case of bovine pancreatic trypsin inhibitor ([Delta]E = -19.8 kcal/mol), leaving no room for a further decrease in entropy from protein tightening. This study illustrates the importance of considering changes in protein flexibility (which in this case favor binding by 3.5 kcal/mol) for the prediction of ligand binding affinities.

NMR structure determination and molecular dynamics simulations are performed to understand the critical interactions between subunits B and F in the [A.sub.1][A.sub.O] ATP synthase of Methanosarcina mazei [G.sup.0]1. Movements of both helices of [B.sub.Mm] are observed to accommodate the incoming C-terminus of [F.sub.Mm] and connect the events of ion pumping and nucleotide binding in the [A.sub.1][A.sub.O] ATP synthase.

The molecular dynamics simulations along with experimental information were used to reproduce experimental trends in binding affinities of the transcription factor p53 peptides with the E3-ubiquitin ligase MDM2. The results offer insight into the origin of ensemble protein-peptide complex and importance of the adaptive surface of MDM2 for drug design.

The studies of papain, the member of the cysteine proteinase superfamily are carried out to demonstrate the role of noncovalent interactions in enzyme active center chemistry. The findings provide insight into the generation of substantial nucleophilic reactivity in the (Cys25)-[S.sup.-]/(His159)-[Im.sup.+]H ion pair by decreasing the level of mutual solvation of the anionic and cationic partners.

The solution studies and crystal structure analysis of N-lithocholyl insulin, in which residue Lys(super B29) has been acylated with a bile acid derivative, are presented. The unit cell in the crystal consists of an insulin hexamer containing two zinc ions, which have two m-cresol molecules, bound at each dimer-dimer interface stabilizing an R6 conformation.

A comparative analysis of properties extracted from two independent molecular dynamics (MD) simulations and from structures determined by Nuclear magnetic resonance (NMR) spectroscopy and X-ray diffraction crystallography (XRD) is presented. The simulations present a view of the dynamics of Rnase Sa that is different but complementary to NMR and X-ray.

The vibrational entropy change on the burial of a crystallographically well-ordered water molecule in bovine pancreatic trypsin inhibitor (BPTI) using normal-mode analysis is dissected. A detailed analysis is performed of how the translational and rotational degrees of freedom of the isolated water molecule are transformed into vibrational modes in the complex.

The addition of a phenol to a hexameric insulin solution leads to the formation of a stable hexamer whose stability arises from a rearrangement in which residues B1-B8 form an (alpha)-helix in the R-state. This R-state, in turn, is partly stabilized by the nonpolar interactions between the phenolic molecule and residue B5 His at the dimer-dimer surface. To test if a tyrosine side chain could mimic the effect of phenol binding and induce the R-state, a B5 His -> Tyr mutant human insulin was constructed. The results showed that it could not since the mutation destabilized the T-state.