Paper Citing NAMD - Abstract
Lockhart, Christopher; Klimov, Dmitri K.
Calcium Enhances Binding of A beta Monomer to DMPC Lipid Bilayer
BIOPHYSICAL JOURNAL, 108:1807-1818, APR 7 2015
Using isobaric-isothermal replica-exchange molecular dynamics and the all-atom explicit-solvent model, we studied the equilibrium binding of A beta monomers to a zwitterionic dimyristoylphosphatidylcholine (DMPC) bilayer coincubated with calcium ions. Using our previous replica-exchange molecular dynamics calcium-free simulations as a control, we reached three conclusions. First, calcium ions change the tertiary structure of the bound A beta monomer by destabilizing several long-range intrapeptide interactions, particularly the salt bridge Asp(23)-Lys(28). Second, calcium strengthens A beta peptide binding to the DMPC bilayer by enhancing electrostatic interactions between charged amino acids and lipid polar headgroups. As a result, A beta monomer penetrates deeper into the bilayer, making disorder in proximal lipids and bilayer thinning more pronounced. Third, because calcium ions demonstrate strong affinity to negatively charged amino acids, a considerable influx of calcium into the area proximal to the bound A beta monomer is observed. Consequently, the localizations of negatively charged amino acids and calcium ions in the A beta binding footprint overlap. Based on our data, we propose a mechanism by which calcium ions strengthen A beta-bilayer interactions. This mechanism involves two factors: 1) calcium ions make the DMPC bilayer partially cationic and thus attractive to the anionic A beta peptide; and 2) destabilization of the Asp(23)-Lys(28) salt bridge makes Lys(28) available for interactions with the bilayer. Finally, we conclude that a single A beta monomer does not promote permeation of calcium ions through the zwitterionic bilayer.
