Folding of Distinct Sequences into Similar Functional Topologies Hossein Mohammadiarani and Harish Vashisth (Advisor) Department of Chemical Engineering,

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Folding of Distinct Sequences into Similar Functional Topologies Hossein Mohammadiarani and Harish Vashisth (Advisor) Department of Chemical Engineering, University of New Hampshire, Durham, NH Abstract Molecular dynamics is a simulation technique to investigate the molecular and atomic interactions by numerical solution of classical equation of motion of all particles. In this work, we study folding of insulin B-chain and its mimetic peptide (RP9- S371) to compare their folding mechanisms. Folding structure of mimetic peptide is yet elusive although it is known that it causes insulin receptor activation. Sequence Alignment Sequence alignment of human insulin B-chain with the insulin mimetic peptides. Residues which are conserved in the alignment between mimetic peptide and the B- chain of human insulin are colored. Mimetic peptide (S371)Insulin B-chain GLY1 SER2 LEU3HSE ASP4LEU GLU5VAL SER6GLU PHE7ALA TYR8LEU ASP9TYR TRP10LEU PHE11VAL GLU12CYS ARG13GLY GLN14GLU LEU15ARG GLY16GLY LYS17PHE LYS18PHE Methods and Software Folding Thermodynamics (Potentials Mean Force) Metadynamics Parameters NAMD (NAnoscale Molecular Dynamics program) is a parallel molecular dynamics code designed for high performance simulation of large systems of particles. VMD (Visual Molecular Dynamics program) is a molecular visualization software for displaying, animation and analyzing the result of MD simulation. Metadynamics is an algorithm for mapping free energy landscape in molecular computations. NAMD is equipped with this algorithm. Simulation time : 100 ns Time step : 1.0 fs hillWidth : 1.0 hillWeight : 0.1 HillFrequency : 1000 Width : 0.2 Two collective variables RMSD = 9.5 (Å) Rg = 18.7 (Å) RMSD = 0 (Å) Rg = 8.7 (Å) Collective variables: Mimetic peptide Native peptide Folding Trajectory Mimetic peptideNative peptide MD Simulation Parameters Peptide immerse d in water box (50 Å x 75 Å x 72 Å) Neutralized in saline water (0.05 mol/L NaCl) Equilibration time : 200 ps, time step : 2.0 fs NPT ensemble with periodic boundary conditions Number of atoms: atoms (including hydrogen) CHARMM 22 force filed with CMAP correction Conclusions Predicted fold of mimetic peptide is highly similar to the known native fold Additional metastable states appear accessible to the native peptide The free-energy differences between the completely unfolded and fully folded states of native and mimetic peptides are comparable These results support the hypothesis that mimetic peptide likely binds to the insulin receptor in same conformation as insulin Methods used are generally applicable to understand folding of other sequences References [1]. Ward CW, et al. Ligand-induced activation of the insulin receptor. Bioessays 31:422–434. [2]. He ́nin, J,et al Exploring multidimensional free energy landscapes using time- dependent biases on collective variables. j. Chem. Theory Comput. 6:35–47. [3]. James C. Phillips, et al, Scalable molecular dynamics with NAMD. Journal of Computational Chemistry, 26: , [4].Humphrey, et al."VMD - Visual Molecular Dynamics", J. Molec. Graphics, 1996, vol. 14, pp Acknowledgment We appreciate the University of New Hampshire for seed funding. Computations were performed on Trillian, a Cray XE6m-200 supercomputer at UNH supported by the NSF MRI program under grant PHY [3] [4] [1] [2]