Comparative Molecular Dynamics Analysis of RNase-S Complex Formation.

Limited proteolysis of RNase-A yields a short N-terminal S-peptide segment and the larger S-protein. Binding of S-peptide to S-protein results in the formation of an enzymatically active RNase-S protein. S-peptide undergoes a transition from intrinsic disorder to an ordered helical state upon association with S-protein to form RNase-S and is an excellent model system to study coupled folding and binding.

Multiscale Simulation of Receptor-Drug Association Kinetics: Application to Neuraminidase Inhibitors.

A detailed understanding of the drug-receptor association process is of fundamental importance for drug design. Due to the long time scales of typical binding kinetics, the atomistic simulation of the ligand traveling from bulk solution into the binding site is still computationally challenging. In this work, we apply a multiscale approach of combined Molecular Dynamics (MD) and Brownian Dynamics (BD) simulations to investigate association pathway ensembles for the two prominent H1N1 neuraminidase inhibitors oseltamivir and zanamivir.

Covalent dye attachment influences the dynamics and conformational properties of flexible peptides.

Fluorescence spectroscopy techniques like Förster resonance energy transfer (FRET) and fluorescence correlation spectroscopy (FCS) have become important tools for the in vitro and in vivo investigation of conformational dynamics in biomolecules. These methods rely on the distance-dependent quenching of the fluorescence signal of a donor fluorophore either by a fluorescent acceptor fluorophore (FRET) or a non-fluorescent quencher, as used in FCS with photoinduced electron transfer (PET). The attachment of fluorophores to the molecule of interest can potentially alter the molecular properties and may affect the relevant conformational states and dynamics especially of flexible biomolecules like intrinsically disordered proteins (IDP).

Transient helicity in intrinsically disordered Axin-1 studied by NMR spectroscopy and molecular dynamics simulations.

Many natural proteins are, as a whole or in part, intrinsically disordered. Frequently, such intrinsically disordered regions (IDRs) undergo a transition to a defined and often helical conformation upon binding to partner molecules. The intrinsic propensity of an IDR sequence to fold into a helical conformation already in the absence of a binding partner can have a decisive influence on the binding process and affinity.

Molecular Dynamics Analysis of 4E-BP2 Protein Fold Stabilization Induced by Phosphorylation.

Protein phosphorylation can affect the interaction with partner proteins but can also induce conformational transitions. In case of the eukaryotic translation initiation factor 4E-binding protein 2 (4E-BP2) threonine (Thr) phosphorylation at two turn motifs results in transition from a disordered to a folded structure. In order to elucidate the stabilizing mechanism we employed comparative molecular dynamics (MD) free energy simulations on the turn motifs indicating that Thr-phosphorylation favors a folded whereas dephosphorylation or substitution by Glu residues destabilizes the turn structure.

Mechanism of pKID/KIX Association Studied by Molecular Dynamics Free Energy Simulations.

The phosphorylated kinase-inducible domain (pKID) associates with the kinase interacting domain (KIX) via a coupled folding and binding mechanism. The pKID domain is intrinsically disordered when unbound and upon phosphorylation at Ser133 binds to the KIX domain adopting a well-defined kinked two-helix structure. In order to identify putative hot spot residues of binding that could serve as an initial stable anchor, we performed in silico alanine scanning free energy simulations.

Adenylylation of Tyr77 stabilizes Rab1b GTPase in an active state: A molecular dynamics simulation analysis.

The pathogenic pathway of Legionella pneumophila exploits the intercellular vesicle transport system via the posttranslational attachment of adenosine monophosphate (AMP) to the Tyr77 sidechain of human Ras like GTPase Rab1b. The modification, termed adenylylation, is performed by the bacterial enzyme DrrA/SidM, however the effect on conformational properties of the molecular switch mechanism of Rab1b remained unresolved. In this study we find that the adenylylation of Tyr77 stabilizes the active Rab1b state by locking the switch in the active signaling conformation independent of bound GTP or GDP and that electrostatic interactions due to the additional negative charge in the switch region make significant contributions.

Exploring biomolecular dynamics and interactions using advanced sampling methods.

Molecular dynamics (MD) and Monte Carlo (MC) simulations have emerged as a valuable tool to investigate statistical mechanics and kinetics of biomolecules and synthetic soft matter materials. However, major limitations for routine applications are due to the accuracy of the molecular mechanics force field and due to the maximum simulation time that can be achieved in current simulations studies. For improving the sampling a number of advanced sampling approaches have been designed in recent years.