Fundamental Structures and Behaviors of Proteins

Abstract

Protein aggregation has been increasingly recognized as a problem limiting the effi cacy and shelf life of protein therapeutics and as an indicator and cause of numerous disease states. Elucidating the molecular mechanisms behind aggregation has become a central focus of investigation in order to improve therapeutics and to understand the relationship between aggregate formation and cellular toxicity in protein misfolding diseases. Innovations in analysis techniques, particularly of solid state materials, and computational molecular modeling approaches have provided higher resolution information about the structure of aggregates as well as key insights into the mechanisms of aggregate formation. These breakthroughs, coupled with understanding gained from solution experiments and biological systems, have just begun to enable strategies to combat aggregation, including the design and evaluation of peptides and small molecules that inhibit the growth or that facilitate the dissociation of aggregates. This chapter describes the fundamental properties of proteins and the current understanding of underlying mechanisms that infl uence native folding and the formation of aggregates.