Molecular dynamics simulations of a fitted multimeric structure of Mycobacterium tuberculosis alpha-crystallin (Mtb Acr) identify solvent exclusion from the beta(4)-beta(8) hydrophobic groove as a critical factor driving subunit assembly. Dehydration is also implicated as a determinant factor governing the chaperone activity of the dimer upon its dissociation from the oligomer. Two exposed hydrogen bonds, responsible for stabilizing the beta(8)-beta(9) fold are identified as key mechanistic elements in this process. Based on the overproduction of the chemokine CXCL16, observed after macrophage exposure to Mtb Acr, the proteases ADAM10 and ADAM17 are mooted as possible targets of this chaperone activity. (C) 2011 Elsevier Inc. All rights reserved.