Identifying Potential Ligand Binding Sites on Glycogen Synthase Kinase 3 Using Atomistic Cosolvent Simulations.

Glycogen synthase kinase 3 ß (GSK3ß) is a serine/threonine kinase that phosphorylates several protein substrates in crucial cell signaling pathways. Owing to its therapeutic importance, there is a need to develop GSK3ß inhibitors with high specificity and potency. One approach is to find small molecules that can allosterically bind to the GSK3ß protein surface. We have employed fully atomistic mixed-solvent molecular dynamics (MixMD) simulations to identify three plausible allosteric sites on GSK3ß that can facilitate the search for allosteric inhibitors. Our MixMD simulations narrow down the allosteric sites to precise regions on the GSK3ß surface, thereby improving upon the previous predictions of the locations of these sites.

Stability of Water Confined between Supported Self-Assembled Monolayers.

We present a thermodynamic argument showing that the evaporation and condensation free-energy barriers of water confined between two hydrophobic self-assembled monolayers (SAMs) vary more gradually with the SAM hydrophobicity as compared to the case of water confined between two bare hydrophobic surfaces (no SAMs). We validate our theory by calculating the free-energy profiles of water confined between two SAMs and between two bare surfaces of different hydrophobicities. An implication of our findings is the existence of three regimes of stability of confined water as a function of the hydrophobicity of the SAMs. In comparison to bare planar surfaces with no SAMs, the highly hydrophobic SAMs act to stabilize the liquid state, whereas weakly hydrophobic SAMs stabilize the vapor state of confined water. For intermediate hydrophobicities, the SAMs reduce both the evaporation and the condensation free-energy barriers. These results imply that the effects of SAM hydrophobicity on the behavior of confined water are nontrivial and richer than previously thought.