Abstract
Confinement is an ubiquitous concept in protein dynamics and studying its effect on protein stability and folding kinetics is necessary to understand protein folding in cellular environments. Confinement easily arises from the crowded in vivo environment that include other proteins and membranes, among others. Effects on the dynamics of the amyloid beta protein of Alzheimer's disease are know to be influenced by it proximity to lipid membranes and other proteins. Here we aim at understanding the relative effects of confinement on the dynamics and folding events of the amyloid beta protein fragment (21-30). For this, we use molecular dynamics in explicit solvent to explore the dynamics of this fragment in differently sized spherical confinement cavities. The different radiuses of the cavities are achieved by dividing the solvent into six different layers of immobile atoms. Starting from a simulation in bulk, each subsequent simulation considers one additional layer of confinement. In this way, the system is slowly taken from bulk to the more confined space. Specifically, starting from a size of 24A we decrease the radius of the confining spherical cavity to a minimum size of 14 A. We measure the change in the free energy of the stretched conformation of the amyloid beta (21-30) by varying the confined cavity size. In addition, we study how this confinement affects the stability of pre-formed beta-hairpin conformations by examining possible conformational changes as a function of time along with the lifetimes of these beta hairpin conformations relative to lifetimes observed in the bulk. Lastly, we present results on mutations of the amyloid beta peptide (21-30) that include the Dutch [Glu22Gln], Arctic [Glu22Gly] and Iowa [Asp23Asn] mutations.
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