title: Mirror images as naturally competing conformations in protein folding.
abstract: Evolution has selected a protein's sequence to be consistent with the native state geometry, as this configuration must be both thermodynamically stable and kinetically accessible to prevent misfolding and loss of function. In simple protein geometries, such as coiled-coil helical bundles, symmetry produces a competing, globally different, near mirror image with identical secondary structure and similar native contact interactions. Experimental techniques such as circular dichroism, which rely on probing secondary structure content, cannot readily distinguish these folds. Here, we want to clarify whether the native fold and mirror image are energetically competitive by investigating the free energy landscape of three-helix bundles. To prevent a bias from a specific computational approach, the present study employs the structure prediction forcefield PFF01/02, explicit solvent replica exchange molecular dynamics (REMD) with the Amber94 forcefield, and structure-based simulations based on energy landscape theory. We observe that the native fold and its mirror image have a similar enthalpic stability and are thermodynamically competitive. There is evidence that the mirror fold has faster folding kinetics and could function as a kinetic trap. All together, our simulations suggest that mirror images might not just be a computational annoyance but are competing folds that might switch depending on environmental conditions or functional considerations.
authors.affiliation: Center for Theoretical Biological Physics and Department of Physics, Rice University, Houston, Texas 77005, USA.
authors.forename: Jeffrey K
authors.initials: JK
authors.lastname: Noel
authors.forename: Alexander
authors.initials: A
authors.lastname: Schug
authors.forename: Abhinav
authors.initials: A
authors.lastname: Verma
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wenzel
authors.forename: Angel E
authors.initials: AE
authors.lastname: Garcia
authors.forename: José N
authors.initials: JN
authors.lastname: Onuchic
mesh_terms: D002942:Circular Dichroism; D007700:Kinetics; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation; D017510:Protein Folding; D011506:Proteins / Q000737:chemistry*; D013816:Thermodynamics
chemical_list: D011506:Proteins