Protein–Ligand Binding Thermodynamics

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· ACS In Focus Bok 4 · American Chemical Society
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Ligand binding by macromolecules represents a core event of broad relevance to a range of systems, including catalytic systems alongside noncatalytic systems such as nucleic acid binding by transcription factors or extracellular ligand binding by proteins involved in signaling pathways. The scope of this primer is constrained to introduce only foundational models without significant discussion of more advanced topics such as allosteric or linkage effects.


Linkage occurs when the binding of a ligand is influenced by the binding of another molecule of the same ligand (homotropic linkage), the binding of a different ligand (heterotropic linkage), physical variables such as temperature or pressure (physical linkage), or changes in macromolecular assembly state (polysteric linkage). Taking this into account, the foundational themes presented in this primer can be used to describe any macromolecule–ligand interaction either by direct use of the models and techniques described here or by applying them to develop more advanced models to explain additional complexities such as those allosteric or linkage effects just mentioned.


The target audience of this primer is the senior undergraduate or junior graduate student who lacks a foundation in ligand-binding thermodynamics. As such, we have focused primarily on foundational thermodynamic treatments and presented only general discussions of relevant experimental designs. Readers of this primer will learn how to build a working understanding of common factors that promote energetic favorability for ligand binding; develop a functional toolbox to understand ligand binding from the perspective of collecting, plotting, and interpreting ligand-binding data; enhance proficiency in deriving thermodynamic mechanisms for ligand binding; and become comfortable in interpreting binding data reported in the literature and independently expanding knowledge beyond the scope introduced in this primer.

Om författaren

Justin M. Miller is an Associate Professor in the Department of Chemistry at Middle Tennessee State University (MTSU). He received his B.S. in chemistry in 2008 and his Ph.D. in chemistry with an emphasis in biophysics in 2013 from the University of Alabama at Birmingham. He completed postdoctoral training in structural biology at St. Jude Children’s Research Hospital in Memphis, TN, before joining MTSU as a faculty member in August 2016.

Justin D. Marsee is a scientist with expertise in ligand-binding thermodynamics and kinetic experimental strategies. He is working on ligand-binding thermodynamics underlying enzymatic recognition of polymer pollutants by enzymes responsible for catalyzing biodegradation. He has engaged in pre-steady-state kinetic studies leading to the knowledge of protein–protein and protein-nucleotide binding mechanisms. He received his B.S. and M.S. degrees in chemistry from Middle Tennessee State University in 2017 and 2020, respectively. He is currently pursuing doctoral studies in Molecular Biosciences at MTSU.

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