Protein chips, devices created by depositing diagnostic proteins onto solid surfaces, have the potential to drastically improve several fields including healthcare, defense, environment and safety, and proteomics. The purpose of the chip is to rapidly detect the identity or abundance of important molecules, such as antibodies, bacteria, and drug targets, in a given sample. Despite the promised advances, the full potential of these devices has not yet been realized as it is difficult to obtain reliable and reproducible results. Chip performance is governed by the ability to place proteins on the surface in a manner that preserves biological activity. This is complicated by the fact that surfaces induce structural changes in proteins that reduce or eliminate function, and no method currently exists to predict the extent of such changes or how function is affected.

Intellectual Merit

The thesis of this proposal is that better protein arrays can be designed from an improved fundamental understanding of the factors affecting protein/surface interactions.

The goals are to 1) create interfacial models that can predict how to tether proteins of interest to various surfaces to achieve maximum ligand-binding ability and 2) outline a set of heuristics to use when designing technologies involving protein/surface interactions. Because current experimental techniques cannot probe surface bound proteins with molecular-level resolution, a modeling and simulation approach is proposed. The basic experimental plan uses advanced sampling methods to probe the stability of proteins and protein/ligand complexes in the bulk and on different types of surfaces. Work includes examining the effects of surface crowding on the function of tethered proteins, stability when tethering in non-loop regions, and changes in folding mechanisms of surface tethered, multistate folders. The work will culminate in modeling complete Protein A/Antibody/Antigen complexes which are important systems in protein chips. To accomplish the goals, a novel coarse-grain model is proposed which is capable of capturing chemically-specific protein/protein and protein/surface interactions a feature that current coarse grain models lack. This model will have the capacity to investigate other systems of interest. The simulation results will be validated using recent experimental measurements of tethered-protein stabilities and surface antibody/antigen binding which have not been available previously. Preliminary work is very encouraging and has shown for the first time that the stability of all alpha, orthogonal bundle proteins on surfaces can be correlated to tertiary structure in a way that facilitates rational design. Overall, the research is expected to result in a detailed, molecular level picture of how surfaces change the structure, stability, and ligand-binding ability of tethered proteins.

Broader Impact

The integrated research and education plan has many inherent levels of impact. Areas that will benefit from an improved understanding of protein/surface interactions include drug design, medical diagnostics, biomaterials, and proteomics. From these will naturally follow additional benefits to society as a whole through better health care.

Aside from these broader societal impacts, this research will have implications on a more local level. Two benefits, improvements in K-12 science education and the promotion of science and engineering as a career, will arise from participation in the NSF sponsored National Center for Engineering and Technology Education (NCETE). Through this effort, teaching modules about the roles proteins and protein/surface interactions will be created to use in the class Career & Technical Education. Other improvements to science education, as well as increased opportunities for underrepresented groups, will occur through outreach programs to local elementary schools with large Hispanic enrollments. Concerning this effort, the PI is proposing the creation of a science room,at Provost Elementary, filled with learning stations, which students will visit on a bi-weekly basis (similar to regular library days).

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Brigham Young University
United States
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