Amyloid fibrillar aggregates of proteins or peptides are involved in the etiology of several neurodegenerative diseases and represent a major problem in healthcare. Short regions in the protein trigger this aggregation. It is important to understand the basis of such short regions aggregation and amyloidosis for therapeutic intervention. In this study, we describe specific physico-chemical properties of amyloidogenic segments and compare them with non-amyloidogenic segments. First, amyloidogenic segments are characterized by lower values for average net charge, electrostatic potential, solvent accessible surface area and B-factor when compared to the non-amyloidogenic segments of the same proteins. Second, they are enriched in hydrophobic residues and have a tendency to form hydrogen bonds. Thus, amyloidogenic segments have distinct physico-chemical properties that are different from those of non-amyloidogenic segments. Third, and quite unexpectedly, our dynamic simulation studies support the hypothesis that amyloidogenic segments have lower average flexibility than non-amyloidogenic segments. Furthermore, the presence of amyloidogenic segments in disordered proteins does not contradict the observation that amyloidogenic segments are less flexible. (C) 2014 The Authors. Published by Elsevier Inc.