Investigating Small-Molecule Ligand Binding to G Protein-Coupled Receptors with Biased or Unbiased Molecular Dynamics Simulations.

An increasing number of G protein-coupled receptor (GPCR) crystal structures provide important-albeit static-pictures of how small molecules or peptides interact with their receptors. These high-resolution structures represent a tremendous opportunity to apply molecular dynamics (MD) simulations to capture atomic-level dynamical information that is not easy to obtain experimentally. Understanding ligand binding and unbinding processes, as well as the related responses of the receptor, is crucial to the design of better drugs targeting GPCRs.

Insights into the function of opioid receptors from molecular dynamics simulations of available crystal structures.

Unlabelled: The opioid receptors are key targets in the treatment of acute and chronic pain, and the development of novel analgesics with reduced side effects is crucial in the search for more effective medications. The crystal structures of opioid receptors have provided a wealth of knowledge on many aspects of opioid receptor pharmacology and function, including ligand binding poses, location of the sodium allosteric binding site, conformational changes associated with activation and putative dimeric interfaces. These crystal structures also offer a starting point for molecular dynamics (MD) simulations to capture one aspect of drug design that static structures cannot resolve, namely protein dynamics.

Impact of Lipid Composition and Receptor Conformation on the Spatio-temporal Organization of μ-Opioid Receptors in a Multi-component Plasma Membrane Model.

The lipid composition of cell membranes has increasingly been recognized as playing an important role in the function of various membrane proteins, including G Protein-Coupled Receptors (GPCRs). For instance, experimental and computational evidence has pointed to lipids influencing receptor oligomerization directly, by physically interacting with the receptor, and/or indirectly, by altering the bulk properties of the membrane. While the exact role of oligomerization in the function of class A GPCRs such as the μ-opioid receptor (MOR) is still unclear, insight as to how these receptors oligomerize and the relevance of the lipid environment to this phenomenon is crucial to our understanding of receptor function.

The effect of a widespread cancer-causing mutation on the inactive to active dynamics of the B-Raf kinase.

Protein kinases play a key role in regulating cellular processes. Kinase dysfunction can lead to disease, making them an attractive target for drug design. The B-Raf kinase is a key target for the treatment of melanoma since a single mutation (V600E) is found in more than 50% of all malignant melanomas.

Folding dynamics of the Trp-cage miniprotein: evidence for a native-like intermediate from combined time-resolved vibrational spectroscopy and molecular dynamics simulations.

Trp-cage is a synthetic 20-residue miniprotein which folds rapidly and spontaneously to a well-defined globular structure more typical of larger proteins. Due to its small size and fast folding, it is an ideal model system for experimental and theoretical investigations of protein folding mechanisms. However, Trp-cage's exact folding mechanism is still a matter of debate.

Confinement-induced states in the folding landscape of the Trp-cage miniprotein.

Although protein folding is typically studied in dilute solution, folding in a cell will be affected by interactions with other biomolecules and excluded volume effects. Here, we examine the effect of hydrophobic confinement on folding of the Trp-cage miniprotein. We used replica exchange molecular dynamics simulations to probe the differences between folding in the bulk, on a hydrophobic surface, and confined between two hydrophobic walls.

Multiple state transition interface sampling of alanine dipeptide in explicit solvent.

We have applied the recently developed multiple state transition interface sampling approach to alanine dipeptide in explicit water. We extract the rate constant matrix for configurational changes between each pair of metastable states. The results are comparable with values from previous literature and show that the method is applicable to biomolecular systems.

The effect of platinum on diffusion kinetics in beta-NiAl: implications for thermal barrier coating lifetimes.

Platinum is added to thermal barrier coatings (TBCs) as it is observed empirically to extend their lifetime, but the mechanism by which Pt acts is unknown. Since Pt has been proposed to alter diffusivities in NiAl, a key component of TBCs, we use first-principles quantum mechanics calculations to investigate atomic level diffusion mechanisms. Here, we examine the effect of Pt on five previously proposed mechanisms for Ni diffusion in NiAl: next-nearest-neighbor jumps, the triple defect mechanism, and three variants of the six jump cycle.