Date of Award

8-2013

Level of Access Assigned by Author

Campus-Only Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

Advisor

Jayendran C. Rasaiah

Second Committee Member

Howard H. Patterson

Third Committee Member

Scott Collins

Abstract

Proteins are biological polymers consisting of polypeptides, chains of amino acids linked together by peptide bonds. The bonds form in vivo at the polypeptide transferase center in the ribosome and leave via a tunnel spanning the length of the large ribosomal subunit. Experiments suggest that helix formation in favorable polypeptides occurs in the lower region of the ribosome tunnel whereas beta sheets and folding occur outside or near the tunnel exit.

This dissertation describes molecular dynamics (MD) simulations of polypeptides in nanotubes open to a water reservoir to mimic the ribosome tunnel and investigate the conditions under which alpha helices form within the tunnel. Helix formation is sensitive to the diameter D of the nanotube and its hydrophobicity, measured by a parameter λ that modulates nanotube peptide interaction. This information was used to construct a phase diagram for helicity as a function of D and λ.

This dissertation explore confinement effects on helix stability of a 23-residue polyalanine peptide and [Glu-(Ala)3-Lys]5 polypeptide confined to either armchair or chiral CNTs open to water reservoirs. I find that Alanine homopolymer (A-23-capped) forms a right-handed α-helix in a 14.9A diameter CNT when λ=1. When λ<1, corresponding to increased hydrophobicity, the diameter with highest helicity shifts down to 13.6A. A-23-capped polyalanine forms an α-helix for diameters between 12.9A and 14.3A in chiral CNTs. A left handed λ-helix forms when D=16.3A and λ= 0.56 to 0.64.

The helicity phase diagram reflects what is known about the lower region of the ribosome tunnel, which is hydrophobic, with an average diameter of 15A. My results differ from earlier simulations using either periodically replicated nanotubes or a course- grained model for water closed to a reservoir. These studies highlight conditions under which alpha helices form in proteins and show the importance of using detailed molecular models for water and an open system in MD simulations of helix formation in confined spaces. If the peptide cannot form its secondary structure, a straight-chain polymer is released at the tunnel exit which cannot form tertiary structures. This information and the conditions for helix formation can be used in designing drugs for use in nanomedicine.

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