Paper Citing NAMD - Abstract
Domene, Carmen; Jorgensen, Christian; Vanommeslaeghe, Kenno; Schofield, Christopher J.; MacKerell, Alexander, Jr.
Quantifying the Binding Interaction between the Hypoxia-Inducible Transcription Factor and the von Hippel-Lindau Suppressor
JOURNAL OF CHEMICAL THEORY AND COMPUTATION, 11:3946-3954, AUG 2015
The hypoxia-inducible transcription factors (HIP) play a central role in the human oxygen sensing signaling pathway. The binding of the von Hippel-Lindau tumor suppressor protein (pVHL)-ElonginC-ElonginB complex (VCB) to HIP-1 alpha is highly selective for the trans-4-hydroxylation form of when Pro564 in the C-terminal oxygendependent degradation domain (ODDD) of HIF-1 alpha. The binding of HIF alpha for VCB is increased by similar to 1000-fold upon addition of a single hydroxyl group to either of two conserved proline-residues. Here, we address how this addition governs selective recognition and characterizes the strength of the interaction of this "switch-like" signaling event. A new set of molecular mechanics parameters for 4-hydroxyproline has been developed following the CHARMM force field philosophy. Using the free energy perturbation (PEP) formalism, the difference in the binding free energies between HIF-1 alpha in the nonhydroxylated and hydroxylated forms with the VCB complex was estimated using over 3 mu s of MD trajectories. These results can favorably be compared to an experimental value of similar to 4 kcal mol(-1). It is observed that the optimized hydrogen bonding network to the buried hydroxyprolyl group confers precise discrimination between hydroxylated and unmodified prolyl residues. These observations provide insight that will aid in developing therapeutic agents that block HIF-alpha recognition by pVHL.
