The Structure of The Laminin Β1 Nonapeptide Probed Through Long-Timescale Temperature Replica-Exchange Molecular Dynamics Simulations in Explicit Solvent

Laminin-1 is a member of a heterotrimeric glycoproteins family belonging to basement membrane. These proteins interact with cell surface receptors involved in adhesion, proliferation, differentiation and angiogenesis processes. The laminin-1 β1 nonapeptide CDPGYIGSR, known also as peptide 11, from domain III of the β1 chain of laminin-1, has been identified as the putative primary binding site for the 67 kDa Laminin Receptor (LR).(1) Overexpression of LR showed strong correlations with poor clinical prognosis in several solid tumors. Because of its critical role in cancer progression, the potential laminin-1 bioactive conformation has been the focus of a number of structural and biological studies. Here, the conformational dynamics of peptide 11 was probed by temperature replica-exchange molecular dynamics (T-REMD) simulations in explicit solvent.(2-3) T-REMD simulations were completed starting from an initial mutated structure of the murine epidermal growth factor peptide (mEGF-(33–42 residues)). Each replica was run for 100 ns. The structural characters were studied based on parameters such as distributions of backbone dihedral angles, free energy surface, stability of folded structure, and favourite conformations. The results showed that the peptide 11 in water adopted two different conformational states: the first state (A) was a bend ensemble with an open β-turn2–5 and nine hydrogen bonds, the second state (B) was a bend ensemble with a open β-turn2-5 and five hydrogen bonds. These findings allowed us to define a pharmacophore model useful for the design of small molecules able to destabilize LR/laminin-1 interaction.