Systematic Studies of Small Cyclic Peptides Using Computational Methods
Abstract: This thesis demonstrates how molecular dynamics simulations can be
used to efficiently sample the conformational ensembles of cyclic peptides and through the
use of systematic studies, begin to elucidate their sequence-structure relationships.
Cyclic peptides are a unique class of molecules, with many interesting properties. However,
the robust application of cyclic peptides is ... read morecurrently limited by our inability to predict
their 3D structures a priori and our poor understanding of their sequence-structure
relationships. After an introduction in Chapter 1, Chapter 2 describes the development of
an enhanced sampling method tailored to cyclic peptides. This methodology works by
exploiting the essential coupled two dihedral angle changes that cyclic peptides undergo
during conformational switches. Chapter 3 describes the use of our enhanced sampling method
to perform systematic studies of cyclic pentapeptides. First, we elucidate the structural
preferences of all 20 natural amino acids within a cyclic pentapeptide template. Then we
determine cooperative effects of neighboring residues to determine key sequence-structure
relationships, ultimately culminating in the design and experimental verification of a
well-structured cyclic pentapeptide in aqueous solution. Chapter 4 describes the systematic
study of simple cyclic hexapeptides, wherein several general rules and interesting
observations are established. In this Chapter another wellstructured sequence in aqueous
solution is identified and its conformation is verified experimentally. Chapter 5 describes
ongoing work where systematic studies of cyclic octapeptides are performed. Within this
work a potentially welliii structured sequence is identified and its robustness as a
template for further design is explored. Lastly, in Chapter 6, I will provide a short
introduction to a separate project on glycopeptides, and describe computational work
towards the design of stable α-helical glycosylation sites using both bioinformatics and
molecular dynamics simulations.
Thesis (Ph.D.)--Tufts University, 2017.
Submitted to the Dept. of Chemistry.
Advisor: Yu-Shan Lin.
Committee: Clay Bennett, Arthur Utz, and Bradley Pentelute.
Keywords: Chemistry, Physical chemistry, and Biophysics.read less