In Camelids (Llamas, Alpacas, Bactrian Camels), a subset of antibodies found in these animals is unique in that the antigen-binding site has only 3 loops and the variable region is thus made by a single-domain denoted VHH (which contrasts with the larger two-domain, 6 loop variable region of conventional antibodies). VHHs thus represent the smallest such structure produced in nature. The goal of this project is to develop a molecular modeling framework to address fundamental questions on the relationship between aminoacid sequence and the structural and dynamical behavior of the binding site of VHH domains. In particular, it is intended to (1) elucidate the key residues and interactions that underlie the appearance of canonical (typical) and non-canonical structures in VHHs and (2) to elucidate the functional relevance of loop flexibility and canonical vs. non-canonical structures on the binding affinity to antigen sites (epitopes).
Broader impacts
This work is expected to help the broad bioengineering community interested in the design of antibodies. Such engineered antibodies are important for novel applications in medicine, separations, and catalysis. Elucidating the structure and dynamics of the active site of antibodies and the way how small antibodies bind ligands and proteins is of key importance to understand their biological function. This work is thus also expected to be complementary to that of scientists who use NMR and x-ray crystal analyses to determine biomolecular structure. The proposed modeling work is synergistic with the experimental work performed by several research groups in the world who have been studying the structure of uncomplexed and complexed VHH systems. This work will gear up a collaboration with a colleague at Cornell who is interested in epitope-mapping studies for antibodies and VHHs. The main educational outcome will be the training of a Ph.D. student during two years, who will get valuable experience working in the growing interfacial area that lies between biology, physics, and computational modeling. In addition, it is expected that at least one Cornell undergraduate researcher will be associated with the project during two regular Semesters. Scientific results will be disseminated through professional meetings and an outreach effort to provide educational software to the local high school. Results from this investigation will be used in at least two classes: a new molecular simulations course and the advanced thermodynamics core course.
