Protein Misfolding Diseases and the Key Role Played by the Interactions of Polypeptides with Water

Abstract

The manner in which a newly synthesised chain of amino acids folds into the unique structure of a functional globular protein depends both on the intrinsic properties of the amino acid sequence and on multiple influences within the crowded aqueous milieu of the cell. But if proteins misfold, or fail to remain correctly folded, a common consequence is aggregation, a phenomenon that is involved in many highly debilitating and increasingly common medical disorders including Alzheimer's disease and Type II diabetes. In this chapter we describe first how the concerted application of a wide range of experimental and theoretical techniques under laboratory conditions has allowed the fundamental principles of protein misfolding and aggregation to be understood at an atomic level. Then we discuss approaches that are designed to explore how these principles apply within living systems. Of particular importance in the context of this volume is the emergence of the role of aggregation propensity, closely linked to the solubility of specific states of proteins in the aqueous environment of the cell, as one of the most fundamental properties that is encoded in the sequences of peptide and protein molecules.