Molecular Dynamics Studies of Protein Targets for Cancer

Abstract

In this meeting, we present the molecular dynamics studies of two protein targets for cancers. The one is epiregulin (EPR), which is a member of the epidermal growth factor family and a factor affecting pancreatic cancer. Recently, it was observed that the binding affinity of EPR without S-S bonds for an antibody is lower than that of EPR with S-S bonds, and that the affinity of a long form type (extracellular domain) of EPR without S-S bonds is higher than that of a mature type without S-S bonds. To investigate the effect of the S-S bonds on the structural stability of EPR, we have performed molecular dynamics (MD) simulation for these three types of EPR. From our simulations, it has found that the S-S bonds reduce the structural fluctuation of EPR, and the structure of the mature domain in the long form type is similar to the mature type with S-S bonds.The other protein target is the loop region between fibronectin type III domains of roundabout-1 that is a receptor for Slit1 and Slit2 in axon growth cones and differentially expressed in cancers. We have investigated the structural stability and thermodynamic property of the loop region using MD simulation. We have calculated two types of peptide of different size: the peptide composed of 26 amino acid residues corresponding to the full region of the fluctuating loop, and the shorter one of 20 amino acid residues. In the 20 amino acid peptide calculations, we have observed two different stable conformations, which are stable during more than 1.5 μs. We have found that for the one conformation, the intramolecular interaction energy contributes to the thermodynamical stability, while for the other one, water binding to the turn part of the peptide is dominant contribution.