Current Research Topics (constantly under construction)
Docking and refinement using evolutionary information
Structural modeling of molecular assemblies lies at the heart of understanding molecular interactions and biological function. We present a method for docking protein molecules and elucidating native-like structures of protein dimers. We use geometric hashing to ensure the feasibility of searching the combined conformational space of dimeric structures. The search space is narrowed by focusing the sought rigid-body transformations around surface areas with evolutionary-conserved amino-acids. Recent analysis of protein assemblies reveals that many functional interfaces are significantly conserved throughout evolution. Our results show that focusing the search around evolutionary-conserved interfaces results in lower lRMSDs.
However, computational docking methods are often not accurate and their results need to be further refined to improve interface packing. We introduce a novel refinement method that incorporates evolutionary information by employing an energy function containing Evolutionary Trace (ET)-based scoring function, which also takes shape complementarity, electrostatic and Van der Waals interactions into account. Our refinement method is able to produce structures with better RMSDs with respect to the known complexes and lower energies than those initial docked structures.
Initial docked solution for 1DS6 has 1546 interface atoms (a), the refined version of the initial docked solution has 1125 interface atoms (b), and the native structure for 1DS6 has 976 interface atoms (c). Interface atoms are drawn as spheres. Chain A is colored in blue and chain B in red.
Characterizing protein-protein and protein-ligand interactions
Neuropilin-1 (NRP-1) is a hub receptor that plays an essential role in angiogenesis, vascular permeability and nervous system development. Previous studies have shown that peptides with an N-terminal Arg, especially peptides expressing the consensus sequence R/K/XXR/K, were expressed in phage libraries expressing peptides for binding to prostate cancer cells. These sequences promoted binding and internalization into tumor cells, while blocking the C-terminal Arg (or Lys) prevented internalization. Such peptides were shown to bind strongly to NRP-1 on the target cells. In this study we investigate the properties of the complex that results from binding of NRP-1 to one of those peptides, RPAR, and perform computational mutant study in order to study the physical, chemical and structural properties of the bound complex and suggest variants that may increase complex binding.
Ribbon representation of the NRP-1 – RPAR complex (left) and a closeup on the binding site (right). Interacting residues are labeled.