SUBJECT: Ph.D. Dissertation Defense
BY: Ahmad Haider
TIME: Tuesday, April 26, 2016, 2:30 p.m.
PLACE: Love Building, 109
TITLE: Direct Measurement of Intermolecular Free Energy Landscapes using Atomic Force Microscope
COMMITTEE: Dr. Todd Sulchek, Chair (ME)
Dr. Peter Hesketh (ME)
Dr. Nazanin Bassiri-Gharb (ME)
Dr. Oliver Brand (ECE)
Dr. Albert Frazier (ECE)


Energy barriers encountered in intermolecular interactions determine outcome of a multitude of key physical, chemical, and biological interactions processes. The energy landscape dictates the specificity and affinity of biological interactions, which is an important target for the development of novel drugs and understanding protein-mediated processes. Determination of free energies has allowed for a number of new insights into chemical processes such as catalysis, phase transformations, and boundary lubrication mechanisms. Despite advances in measuring interaction forces, determining energy landscapes at nanometer dimensions remains a challenge. Computer simulation techniques do provide a useful approach for estimating free energy landscapes, but only to the limit of the accuracy of the model potentials and the integration of the equations of motion. Indirect experimental approaches such as dynamic force spectroscopy measurements, though useful in determination of kinetic constants such as off rates and barrier widths, do not completely determine the shape or curvature of the energy landscape. Emergence of ultrasensitive force detection techniques such as atomic force microscope (AFM) has proved invaluable in direct determination of energy landscapes since it combines excellent force and distance resolution with the ability to probe local interactions at nanoscale levels. In this thesis, we have developed a technique using AFM to directly map the intermolecular free energy landscape of biological and chemical interactions. The method utilizes the Brownian (thermal) fluctuations to vibrate a sensitive cantilever through the energy profile between the tip and surface. By recording subtle deviations from the harmonic cantilever vibrations and transforming them to energy using Boltzmann distribution, the free energy landscape can be reconstructed. We have further improved on the technique to be able to sample interactions where the gradient of attractive forces is very high in comparison to cantilever stiffness. This would normally result in the cantilever becoming unstable and getting trapped in the energy well. By exciting the cantilever with white noise, we have maintained Boltzmann-like sampling of the energy landscape and avoid getting trapped for long periods of time.