Biomedical subjects

Ute F Röhrig

Publications and source records attributed to Ute F Röhrig.

5 recordsLinked to original sources

PubMed2006

Stability and structure of oligomers of the Alzheimer peptide Abeta16-22: from the dimer to the 32-mer.

Several neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's diseases are associated with amyloid fibrils formed by different polypeptides. We probe the structure and stability of oligomers of different sizes of the fragment Abeta(16-22) of the Alzheimer beta-amyloid peptide using atomic-detail molecular dynamics simulations with explicit solvent. We find that only large oligomers form a stable beta-sheet aggregate, the minimum nucleus size being of the order of 8-16 peptides. This effect is attributed to better hydrophobic contacts and a better shielding of backbone-backbone hydrogen bonds from the solvent in bigger assemblies. Moreover, the observed stability of beta-sheet aggregates with a different number of layers can be explained on the basis of their solvent-accessible surface area. Depending on the stacking interface between the sheets, we observe straight or twisted structures, which could be linked to the experimentally observed polymorphism of amyloid fibrils. To compare our 32-mer structure to experimental data, we calculate its x-ray diffraction pattern. Good agreement is found between experimentally and theoretically determined reflections, suggesting that our model indeed closely resembles the structures found in vitro.

Amyloid beta-Peptides↗

PubMed2005

Solvent and protein effects on the structure and dynamics of the rhodopsin chromophore.

The structure and dynamics of the retinal chromophore of rhodopsin are investigated systematically in different environments (vacuum, methanol solution, and protein binding pocket) and with different computational approaches (classical, quantum, and hybrid quantum mechanics/molecular mechanics (QM/MM) descriptions). Finite temperature effects are taken into account by molecular dynamics simulations. The different components that determine the structure and dynamics of the chromophore in the protein are dissected, both in the dark state and in the early photointermediates. In vacuum and in solution the chromophore displays a very high flexibility, which is significantly reduced by the protein environment. In the 11-cis chromophore, the bond-length alternation, which is correlated with the dipole moment, is found to be similar in solution and in the protein, while it differs greatly with respect to minimum-energy vacuum structures. In the model of the earliest protein photointermediate, the highly twisted chromophore shows a very reduced bond-length alternation.

Molecular Structure↗

PubMed2004

A molecular spring for vision.

Light absorption by the visual pigment rhodopsin leads to vision via a complex signal transduction pathway that is initiated by the ultrafast and highly efficient photoreaction of its chromophore, the retinal protonated Schiff base (RPSB). Here, we investigate this reaction in real time by means of unrestrained molecular dynamics simulations of the protein in a membrane mimetic environment, treating the chromophore at the density functional theory level. We demonstrate that a highly strained all-trans RPSB is formed starting from the 11-cis configuration (dark state) within approximately 100 fs by a minor rearrangement of the nuclei under preservation of the saltbridge with Glu113 and virtually no deformation of the binding pocket. Hence, the initial step of vision can be understood as the compression of a molecular spring by a minor change of the nuclear coordinates. This spring can then release its strain by altering the protein environment.

Algorithms↗

PubMed2003

QM/MM Car-Parrinello molecular dynamics study of the solvent effects on the ground state and on the first excited singlet state of acetone in water.

We present a hybrid Car-Parrinello quantum mechanical/molecular mechanical (QM/MM) approach that is capable of treating the dynamics of molecular systems in electronically excited states in complex environments. The potential energy surface in the excited state is described either within the restricted open-shell Kohn-Sham (ROKS) formalism or within time-dependent density functional theory (TDDFT). As a test case, we apply this technique to the study of the solvent effects on the ground state and on the first excited singlet state of acetone in water. Our results demonstrate that for this system a purely classical description of the solvent is sufficient, since inclusion of the first solvent shell of 12 water molecules into the quantum system does not show a significant effect on this transition. The excited-state energies calculated with ROKS are red shifted by a constant value compared to the TDDFT results, while the relative variations of the excitation energy for different configurations are in very good agreement. The experimentally observed blue shift of the excitation energy in going from gas phase to condensed phase is well reproduced. Excited-state dynamics carried out with ROKS yield the relaxation of the solute and the rearrangement of the solvent structure on a picosecond timescale. The calculated Stokes shift is in reasonable agreement with experimental data.

Journal Article↗

PubMed2002

Early steps of the intramolecular signal transduction in rhodopsin explored by molecular dynamics simulations.

We present molecular dynamics simulations of bovine rhodopsin in a membrane mimetic environment based on the recently refined X-ray structure of the pigment. The interactions between the protonated Schiff base and the protein moiety are explored both with the chromophore in the dark-adapted 11-cis and in the photoisomerized all-trans form. Comparison of simulations with Glu181 in different protonation states strongly suggests that this loop residue located close to the 11-cis bond bears a negative charge. Restrained molecular dynamics simulations also provide evidence that the protein tightly confines the absolute conformation of the retinal around the C12-C13 bond to a positive helicity. 11-cis to all-trans isomerization leads to an internally strained chromophore, which relaxes after a few nanoseconds by a switching of the ionone ring to an essentially planar all-trans conformation. This structural transition of the retinal induces in turn significant conformational changes of the protein backbone, especially in helix VI. Our results suggest a possible molecular mechanism for the early steps of intramolecular signal transduction in a prototypical G-protein-coupled receptor.

Animals↗