Research

We study how outer membrane proteins fold for the purpose of developing cancer therapeutics, novel vaccines, and methods of environmental remediation.

Our lab is cross-disciplinary, bringing together computational biology, protein design, and molecular biology approaches. We assess the structural bioinformatics of OMPs (outer membrane proteins) and apply the results to de novo OMP protein design and to native OMP manipulation.

OMPs are a ripe target for cancer therapeutics. Mitochondria have recently become a focus of cancer therapies due to the fact that mitochondrial outer membrane permeabilization leads to apoptosis or necrosis. We explore mitochondrial membrane permeabilization through manipulation of the OMP pores that already exist in the mitochondrial outer membrane. This may have pharmaceutical consequences because tumorigenic mitochondrial membranes can be selectively targeted in themselves as they have been shown to accumulate lipophilic cations.

Beyond this mechanistic understanding, knowledge of the relationship between OMP chemistry and structure will allow new OMPs to be designed for use in vaccines and will facilitate manipulation of native bacterial OMPs for custom tailored drug delivery systems that could shorten bacterial infections. Outer membrane proteins have been used for the development of vaccines in three distinct ways: as antigens, as adjuvants and as fasteners to conjugate soluble antigens to outer membrane vesicles. Finally, because OMPs are the bacterial import machinery, drugs could be designed in such a way to manipulate OMPs such that those drugs can facilitate their own import into bacteria.

Finally, OMPs also hold great promise for environmental applications. OMPs combine topical accessibility with pore function and/or catalytic function. This combination allows novel OMPs to lead to engineered bacteria that would utilize alternative carbon sources. Designed OMPs could allow bacteria to attach to and degrade unwanted materials. In an environmental application, designed membrane proteins could assist with landfill minimization by allowing bacteria to use polyethylene plastics as a carbon source. Additionally, soil bacteria OMPs could be designed to degrade TNT enabling the deactivation of landmines. By determining many fundamental aspects of how nature forms OMPs we aim to demonstrate how scientists can manipulate these proteins.

Figure3v9_gb_med
Bioinformatics leads to understanding function: Average hydrophobicity correlates with the structure of the membrane. a) The average hydrophobicity for each 2Å of outward-facing barrel amino acids as a function of position in the membrane. b) A MDs simulation of the outer membrane (Shroll and Straatsma,2002) displaying how the membrane is configured as a function of z. c) Schematic of the composition of the outer membrane. Phospholipid shown in light gray—head groups are circles and acyl chains are zigzag lines. Most of the LPS is shown in dark gray except for the phosphates, which are shown in yellow. Sugars are shown as hexagons and acyl chains as zigzag lines. J.S.G. Slusky and R.L. Dunbrack. Bioinformatics (2013 )