Journal:JBSD:12

Analysis of Delta–Notch interaction by molecular modeling and molecular dynamic simulation studies

Riddhi Majumder, Sujata Roy, Ashoke Ranjan Thakur ^[1]

Molecular Tour
Delta-dependent Notch signaling regulates a host of physiological processes. Delta and Notch is known to interact with each other but little is known about the interfaces of interaction and the resulting structure of the complex. Here we have studied the interaction of Delta-Notch by Molecular modeling and Molecular dynamic simulation. The known crystal structure of mammalian Notch1, having homology to Drosophila Notch protein, has 36 EGF-like repeats. Each repeat is composed of approximately 40 amino acids and its structure is defined by six conserved cysteine residues that form three conserved disulfide bonds. A part of interacting Delta protein (Drosophila) from sequence number 183-330 has sequence similarity with human Jagged-1 DSL domain and EGF S1-3. This taking 2vj2 as a template. The ligand binding part of Notch1 (PDB ID: 1toz) comprises of 3 EGF-like repeats which interacts with Delta. Experimental results indicate that V453 and G472 of Notch represent the strongest candidate for binding. These residues were used as constraint during docking. and , of all obtained after docking were selected based on interaction energy and ∆ASA used for further analysis. Notch ligand binding region and Delta are shown in red and blue, respectively. Yellow and cyan residues indicate the positions of V453 and G472 residues of Notch. Interface residues are defined as those residues that have an Accessible Surface Area (ASA) which decreases by >1.0 (Å)² on complex formation. In Model-X there are nine interface residues compared to six in Model-I. The distance between V453 of Notch and DSL residues namely F196, R198, R200 and F204 was analyzed. After MD simulations F196, R198 and R200 residues of Delta comes closer to V453 especially in Model-X. Residues F196 and R198 of Delta come closer to G472 of Notch in Model-X.

Further in both models the interactions are Van der Waal’s with one or two strong electrostatic interactions. The interface of Model-X, analyzed by PROTORP server is more planar (Planarity =2.2 Å) than Model-I (Planarity =3.8 Å). It has been suggested that heterocomplexes have interfaces that are more planar than the homodimers thus from the analysis Model-X is preferred. In Model-I the solvation energy gain is -0.1 Kcal/mol for Delta and -0.0 Kcal/mol for Notch which increases to -1.5 Kcal/mol and -1.8 Kcal/mol respectively after MD simulation. On the other hand, solvation energy gain on complex formation in Model-X (after docking) is -4.6 Kcal/mol for Delta and -4.3 Kcal/mol for Notch which decreases to -3.3 Kcal/mol and -3.2 Kcal/mol respectively after MD simulation. (Structure of Model-I and Model-X after simulation)

In conclusion from planarity of the docked structure, distances between Delta and Notch residues, favorable solvation energy gain, it appears that Model-X is a better fit and provides a compact structure for Delta-Notch interaction. This in turn will help understand the easy packing of these structures in a membrane pit during endocytosis.