Proteins have many structural and mechanical roles in the body from collagen in bones to titin in muscles and from integrin on the cell surface to ion channels within cell membranes. Recently, it has been shown that special Atomic Force Microscopes, """"""""pullers,"""""""" can be used to measure the mechanical properties of individual molecules by pulling on them. The force vs. distance curves from these pullers contain information about bonds within molecules and about bonds between molecules. This information could lead to a deeper understanding of pathologies associated with the structural and mechanical properties of proteins and give insight into possible remedies. There are, however, problems with the existing pullers that are available for general use. As examples: 1) the force noise in the pullers currently used for this work is significantly larger than it needs to be, obscuring subtle features due to weak bonds. 2) Existing pullers do not combine the Atomic Force Microscope's imaging abilities for selecting molecules together with accurate sensors to measure the distance of pulling. Other problems are detailed in the body of the proposal. Work is proposed here to improve the instruments that are available for general use by three stages of instrument development: (1) adding small cantilever capability for increased force resolution (a factor of 5) and increased speed (a factor of 30) while retaining accurate position measurement and imaging, (2) adding optical access for microscope objectives with high numerical aperture and (3) moving only the cantilever in both pulling and imaging to avoid high frequency shaking of delicate samples like cell cultures.
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