Figure 1: 3D representation of water coordination (1a) and displacement (1b) and the corresponding molecular footprints regarding to electrostatic interaction energy (1c, d).
Figure 2: HER2 kinase domain in different activation states (conformations): fully active (2a), active-like (2b) and CDK/Src-like inactive (2c) indicated by structural elements such as helix αC and the activation loop (A-loop).
Figure 3: A ribbon/surface representation of the asymmetric dimer between ErbB receptors (activator = HER3, receiver = EGFR, PDB# 4RIW). Subtrates in the ATP-binding pockets shown in green.
Project #1: Develop a virtual screening protocol using DOCK6 and AMBER software suite that coordinates (Fig. 1a) or displaces (Fig. 1b) bridging water molecules (i.e. binding site waters that mediate hydrogen bonding between ligands and protein receptors) using solvated molecular footprints (per-residue decomposed interaction energy maps, Fig. 1c, d). One can rationally design ligands with polar functionalities that coordinate or displace these water molecules and thus mimic the key interactions mediated by these waters.
Project #2: Identify novel small-molecule inhibitors that are specific to several activating somatic mutants of human epidermal receptor 2 (HER2), which is a receptor tyrosine kinase that participates in regulation of cell proliferation and migration (Fig. 2). Some somatic mutants of the HER2 kinase domain have been shown with deregulated kinase activity and thus oncogenic in breast cancer. For each HER2 mutant of interest, I am going to develop an atomic-level homology model and use virtual screening (to predict binding geometries and energy of each small molecule in an in silica library to the protein target) to identify specific inhibitors for biochemical testing by our collaborator.
Project #3: Explore the structural mechanism of HER2 activation in the context of "head-to-tail" asymmetric heterodimers (Fig. 3) with other ErbB family receptors (i.e. EGFR, HER3 and HER4), where the receiver monomer gets activated by the activator in an allosteric way, using molecular dynamics (MD) simulations with enhanced sampling methods such as accelerated MD.