Antibody Paratope States in Solution

Antibodies are a central part of the adaptive immune system, which is responsible for defending against pathogens such as viruses and bacteria in the human body. An essential process of the immune system is the affinity maturation of antibodies, which occurs after the first contact with the antigen. During affinity maturation, through multiple rounds of somatic hypermutation, antibodies with higher specificity and affinity are produced by the body. This leads to a very precise and efficient detection of pathogens, but also results in a lower effectiveness of this immune response in the case of mutations in viruses or other pathogens. This problem is becoming obvious due to the current deve lopment of the coronavirus pandemic. The immunity of both recovered and vaccinated individuals is compromised by viral mutations due to the high specificity of antibodies directed by the body against the virus. In the past few decades, interest in the commercial production of antibodies in the pharmaceutical industry has risen sharply, as their long half-lives, high specificities and binding properties make them particularly suitable as therapeutic agents. In particular, the successes in the treatment of cancer and autoimmune diseases have meant that a large part of the global sales of the pharmaceutical industry is achieved with so-called biologics, which are mostly therapeutic antibodies. Until now, it has been assumed that the binding region the paratope of antibodies is restricted to a static canonical conformation that determines their binding properties. In this project we plan to escape from this paradigm of static canonical structures. In preliminary work, we were already able to show that it is the dynamics of the binding region that is responsible for the binding properties and specificity of antibodies. By expanding the repertoire of state-of-the-art simulation techniques, we want to achieve, for the first time, a complete description of the conformations, thermodynamics, and kinetics of the entire binding region in solution. These findings will have far -reaching implications for the field of antibody design and biotherapeutic development as they provide a new understanding of the binding site, antibody-antigen recognition and their respective dynamics. We plan to use binding region dynamics to improve structure prediction and understanding of antibody binding properties and specificity. The knowledge gained will also be used to optimize the characteristics important for the production and action of antibodies. In addition, a better understanding of these properties will help to better predict the recognition of mutant pathogens and to perfectly match the specificity of therapeutic antibodies again st pathogens and their mutations. The project takes place at the Center for Chemistry and Biomedicine under the direction of Klaus R. Liedl, who has many years of experience and a very successful track record in the field of computer simulation techniques and antibody research. Klaus Liedl`s staff are very experienced in applying the theoretical techniques described in this proposal. At the same time, the available advanced computer infrastructure guarantees an efficient workflow.