(6hf) Optimization of Protein/Peptide Electrostatic Properties for Bioengineering Applications

If current technological trends continue, significant advancement in the area of biomolecular engineering is needed, since the ability to manipulate macromolecules, e.g. proteins, for novel purposes is central to many problems in bioengineering and medicine. Proteins are complex biomolecules with intricate three-dimensional structures stabilized through networks of noncovalent interactions, including hydrogen bonds, Van der Waals forces, and electrostatics. In particular, electrostatic interactions contribute significantly to protein structure, dynamics, and consequently function (1), especially the pH-dependent aspects of function such as association, stability, and catalysis (2). Much of my previous work has been focused on developing tools for analysing the role of electrostatics in protein function (3-7), and how to manipulate the electrostatic character of proteins for improved function (8-9).

Future areas of interest are centered around the development and application of methods for optimizing electrostatic interaction networks, with specific focus on engineering pH-dependent properties of proteins/peptides. Global optimization, including data driven methods, will be an essential component for tackling the significant combinatorial complexity of the protein design problem. Such methods could be applied to the design of more stable therapeutic antibodies, or the design of novel enzymes for the production of biofuels. Another area of great interest is the development of peptide-based technologies, such as antimicrobial/cell penetrating peptides, pH-sensitive peptide materials, or peptide catalysts, which would be produced using solid-phase peptide synthesis.   

1. Gorham, R., Kieslich, C. A., and Morikis, D. (2011) Electrostatic clustering and free energy calculations provide a foundation for protein design and optimization. Ann. Biomed Eng, 39(4): 1252-63.

2. Kieslich, C.A.*, Tamamis, P*, Gorham, R.D., López de Victoria, A., Sausman, N.U., Archontis, G., Morikis, D. (2011) Exploring protein-protein and protein-ligand interactions in the immune system using molecular dynamics and continuum electrostatics. Curr. Phys. Chem., 20(2):324-343.

3. Kieslich, C.A., Yang, J., Gunopulos, D., and Morikis, D. (2011) Automated computational protocol for alanine scans and clustering of electrostatic potentials: application to C3d.CR2 association. Biotech. Prog., 27(2): 316-325.

4. Kieslich, C.A., Gorham, R.D., and Morikis, D. (2011) Is the rigid-body assumption reasonable? Insights into the effects of dynamics on the electrostatic analysis of barnase-barstar. J. Non-Cryst. Solids, 357(2): 707-716.

5. Kieslich, C.A. and Morikis, D. (2012) The two sides of complement C3d: Evolution of electrostatics in a link between innate and adaptive immunity. PLoS Comp. Bio., 8(12): e1002840.

6. Kieslich, C.A., Shin, D., López de Victoria, A., González-Rivera, G., Morikis, D. (2013) A predictive model for HIV-1 co-receptor selectivity and disease progression. AIDS Res. Hum. Retroviruses, 29:1386-1394.

7. Kieslich, C.A., Goodman, G., Vazquez, H., López de Victoria, A., and Morikis, D. (2011) The effect of electrostatics on Factor H function and related pathologies. J. Mol. Graph Mod., 29(8): 1047-55.

8. Pyaram, K., Kieslich, C. A., Yadav, V. N., Morikis, D., and Sahu, A. (2010) Influence of electrostatics on the complement regulatory functions of Kaposica, the complement inhibitor of Kaposi.s sarcoma-associated herpesvirus. J.Immunol., 184(4): 1956-1967.

9. Liu, Y., Kieslich, C.A., Morikis, D., Liao, J. (2014) Engineering pre-SUMO4 as efficient substrate of SENP2, Protein Eng. Des. & Sel., 27, 117-126.