Thermodynamic Origin of the Affinity and Selectivity of Biomolecules for Metals

Researchers from Dartmouth are quantifying how tightly and selectively proteins and other biological molecules bind metals to a) understand metal transport in biological pathways, b) provide unique high-quality data for computational analysis of biological processes, and c) obtain new insight for potential biotechnology applications. Living organisms require several essential metals (e.g., iron, zinc, copper) but are exposed to several toxic metals (e.g., mercury, lead, cadmium). Understanding how they manage their requirement for the former and avoid the toxicity of the latter is an important challenge. Since proteins play a central role in acquiring and managing essential metals, as well as sequestering and removing toxic metals, this research will quantify metals binding to key proteins. It will also investigate metals binding to unique sequences of DNA, thereby expanding the impact of this research. The research team will use its unique ability with experimental techniques and data analysis to obtain rigorously accurate values for the thermodynamics that determine the affinity of biological molecules for metals. Their discoveries will provide important insight on biological processes as well as widely useful data and means to collect useful data for computational efforts and for AI/ML models. In addition, this research will provide valuable training for graduate students in modern data acquisition and analysis important for the STEM workforce of the 21st century. This project aims to quantify the fundamental molecular basis for the metal-binding affinity and selectivity of proteins and other biological molecules, including unique DNA sequences with metal-specific catalytic activity (DNAzymes) and the potential for applications in sensing and quantifying metals in living organisms and the environment. In addition to quantifying the binding enthalpy and binding entropy for metals binding to proteins, this research will create a database of these values for individual amino acids binding to metals. These data will enable both experimental and computational analysis to quantify the unique outer sphere contributions of a protein to its affinity for metals. Measurements on electron-transfer metalloproteins will reveal the thermodynamic contributions (enthalpy, entropy) that modulate the affinity of the protein for the metal in its oxidized and reduced states and, thereby, tune the reduction potential of the protein for its role in electron transfer. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.