Our understanding of the structural basis for protein function is rapidly evolving as a result of modern approaches to structural proteinomics. Our intention is to use this understanding as a starting point for the design of biomimetic polymers that are much more stable and inexpensive to produce than natural proteins, but nevertheless mimic their key biological properties. A primary goal of this project will be to design polymers and defined-length oligomers capable of presenting functional groups in arrays similar to those found in natural, biologically active proteins. To illustrate this approach, we will design mimics of a class of membrane-active antimicrobial peptides and proteins. A large class of antimicrobial peptides adopt positively charged amphiphilic alpha-helices, in which charged, polar groups and apolar groups line up on opposite faces of the helical cylinder. We recently synthesized a series of mimics of these helices based on Beta-amino acids rather than alpha-amino acids. Here, we propose to use these highly simple beta-peptides as frameworks for further elucidating how chain length, helical potential, charge density, and hydrophobicity affect antimicrobial activity. Further, we propose to develop computational methods to aid in the design and analysis of a variety of other antimicrobial polymers that are simpler in structure and hence much less expensive to produce than either alpha- or Beta-peptides. The antimicrobial activities of these polymers will be tested in solution and when attached to solid surfaces. The structures and mechanisms of action of the polymers and oligomers will be evaluated using a battery of biophysical methods, as well as by using gene chips to examine which genes are turned on by sub-lethal concentrations of the compounds.
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| Pophristic, Vojislava; Vemparala, Satyavani; Ivanov, Ivaylo et al. (2006) Controlling the shape and flexibility of arylamides: a combined ab initio, ab initio molecular dynamics, and classical molecular dynamics study. J Phys Chem B 110:3517-26 |
