Modeling of Biomolecular Systems Interactions, Dynamics, and Allostery: Bridging Experiments and Computations - September 10-14, 2014, Istanbul, Turkey

Modeling of Biomolecular Systems Interactions, Dynamics, and Allostery Poster Session I

22-POS Board 22 Computational Analysis of Biopharmaceuticals Stability for Early Prediction of Manufacturability Nesrine Chakroun , Paul A. Dalby. University College London, London, United Kingdom. Biopharmaceuticals or therapeutically relevant proteins have become one of the fastest growing parts of the pharmaceutical industry. These innovative molecules are more complex than conventional drugs and their processing is much more demanding.The analytical characterization of these new drugs is a fundamental step in the early prediction of their behavior in bioprocesses. This research project aims to develop a framework to improve candidate design and selection at early stages of development by establishing a set of critical analysis and identifying key properties (intrinsic and extrinsic) allowing the prediction of candidates behaviour in large-scale bioprocesses. Our multidisciplinary approach combines the computational analysis (sequence analysis, Molecular Dynamics simulations and docking) and the biophysical characterization of a set of Fragment antibody (Fab) mutants. This allowed the identification of several regions of unstable structure which could be targeted to enhance candidate’s stability. The effect of formulation was also investigated highlighting the role of electrostatics in Fab stability and folding. Additionally, aggregation kinetics studies were carried out at a wide range of temperature, pH and ionic strength allowing the determination of a model for Fab aggregation. These data are used as early indicators for protein stability and to create indices for product manufacturability

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