Computationally Aided Rational Design of Foldamers
and its Applications
Our research group has been developing an approach that allows structure predictability of an important class of foldamers, oligomers that fold into well-defined secondary structures in solution, and have potential in a variety of novel applications. The main objective of the work is to modify computational tools for accurate prediction of foldamer structures, and to establish information transferability between the foldamer building blocks and the final foldamer structure.
The group focuses on arylamide foldamers, with special attention to specific features of foldamer building blocks and non-covalent interactions between monomers that are crucial for arylamide foldamer structure control, i.e. for conformational properties at the oligomer level. We approach many diverse applications of foldamer design:
A variety of novel ‘‘apple peel’’ shaped helical arylamide capsules have been experimentally pursued due to their flexible nature and designability. We have been working on already known systems, as well as possible modifications of the capsules. For example, using molecular dynamics simulations with our new aryl-amide force field parameters, we identified ligand binding/release mechanisms for a class of arylamide capsules, in which the capsule’s helical structure is either minimally disturbed or restored quickly. Furthermore, we determine the effects of ligand sizes, their chemical nature (hydrogen bonding capabilities), and solvents on capsule binding modes and stabilities.
Foldamer Helix Handedness Inversion
Handedness of helical molecules affects both their structure and function. Handedness inversion of helical arylamides is of particular interest to our group due to its role in revealing information on the stability of helix structures and in the design of helical capsules for diastereoselective encapsulation of chiral ligands. Various aspects of foldamer handedness inversion have been examined by experimental methods, facilitating our work. We study handedness inversion mechanism using metadynamics method and our modified force field parameters, with the goal of obtaining the free energy of handedness. So far, we have demonstrated that, to change their handedness, arylamide helices do not need to fully unfold; rather, they go through a stepwise pathway, where each step consists of a previously unfolded dihedral angle folding into the opposite handedness, and its adjacent dihedral angle unfolding in preparation for the next step.
DNA Binding of Cyclic Polyamides
Polyamides have been experimentally designed to sequence-specifically bind to the DNA minor groove and disrupt protein-DNA interactions of medically important transcription factors, influencing thus their overexpression, a distinguishing feature of many types of cancers. Using our computational approach, we address how dynamic perturbations of DNA grooves and DNA bending upon ligand binding influence conformational flexibility in both the double helix and polyamides, and what roles various features of polyamides play in the binding.