MD Studies of Peptide Secondary Structure

Joyce Peng, Vaidehi Nagarajan, William A. Goddard, III

Abstract:

Part I: Effect of substitutions and different chain lengths on alpha- -helix formation.

We present a series of NEIMO TVN molecular dynamics of the alpha-helix formation using poly(L-alanine) starting at extended conformation. Each simulation was done at 450 K with implicit solvent for 500 ps. The middle Ala residue of the poly(L-alanine) 20 mer were substituted with Leu and Gln. 129 out of 155 trajectories (83%) of poly-Ala 20mer formed persistent alpha-helix, while 33 out of 43 trajectories (77%) of the peptide with Leu substitution and 30 out of 44 trajectories (68%) of the peptide with Gln substitution formed persistent alpha-helix within 500 ps simulation time. Our result corresponds with experimental helix propensity. Gln sidechain was observed to be able to block helix propagation in most of the cases, and induce nucleation occasionally through its ability to form hydrogen bonds with backbone atoms.

 

We also did 10 simulations for each different chain length of poly-Ala peptide and analyzed the percentage of residues with torsional angles in the alpha-helical region during the last 5 ps of the simulation time (totally 500 ps). We found that 15mer is the optimal length for poly-Ala for helix formation. A helix that is too short (e.g. 5 mer) fluctuates fast between the helix and coil forms. While a helix that is too long (e.g. 40 mer) has more chances to form non-local hydrogen bonds, which retard helix propagation, or to be trapped in other non-helical secondary structures.

 

We also observed antiparallel beta-hairpin conformation in some of the trajectories. We'll represent in the talk a single trajectory in which an antiparallel beta-hairpin first formed and gradually transforms to an alpha-helix. Beta-hairpin formation explains the first energy drop while the alpha-helixformation accounts for the second energy drop. In our simulation, alpha-helix conformation is more stable than beta-hairpin conformation. This trajectory might give some insight to secondary structure transition common to several diseases.

 

Part II: Comparison of the beta-sheet stability between crystals with pure Gln and crystals with 50% Gln and 50% Arg - searching for possible cures for Huntington's disease (HD).

HD is an inherited, neurodegenerative disorder caused by the expansion of a glutamine repeat in the N-terminus of the huntingtin protein. Poly-gln has been suggested to form fibers composed of beta-sheet conformation and Arg has been suggested to decrease the fiber formation. We did 10 ps simulations for each temperature from 700K to 1500K with 100K interval (starting from the same initial structure for each temperature) using an infinite crystal (infinite beta-sheet) composed of 100% Gln and an infinite crystal composed of 50% Gln and 50% Arg. In our current analysis, these two crystal exhibit similar stabilities with respect to temperature.

Supporting agencies: Caltech biology department, NIH, NICHD