Thermodynamics of β-Structures from Molecular Dynamics Simulations

Abstract

β-Sheets are some of the most common secondary structure motifs in proteins, and are important for mediating protein-protein interactions through their association. This association can also lead to the aggregation of misfolded proteins into β-pleated-sheets in neurodegenerative disorders like amyloidosis. The folding pathway from random coil to β-sheet usually involves two competing process: (1) the collapse of a hydrophobic core, and (2) the formation of intrapeptide hydrogen bonds. It has been proposed, and shown computationally, that the hydrophobic core collapse precedes hydrogen bond formation. In this study we examine the thermodynamics of β-hairpin formation for the GB1 domain of protein G with molecular dynamics simulations by calculating a two-dimensional free energy surface in both vacuum and explicit water using as our reaction coordinates (1) the radius of gyration of the hydrophobic core and (2) the number of native hydrogen bonds, corresponding to the two aforementioned folding processes, respectively. We also compare the results of different versions of the CHARMM force field, namely CHARMM22, CHARMM22/CMAP, CHARMM22∗ and CHARMM36. Finally, we show how these methods can be applied to other β-structures in vivo, namely β-helix structures in the outer membrane of Gram-negative bacteria.