Journal
JOURNAL OF PHYSICAL CHEMISTRY B
Volume 116, Issue 23, Pages 6880-6888Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jp212623d
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Funding
- Center for Theoretical Biological Physics
- National Science Foundation (NSF) [PHY-0822283]
- NSF [NSF-MCB-1214457, NSF-MCB-1050966]
- Cancer Prevention and Research Institute of Texas
- Impuls of the Helmholtz Association of German Research Center
- BW Stiftung Grant [HPC-5]
- Vernetzungsfond of the Helmholtz Association of German Research Center
- Direct For Biological Sciences
- Div Of Molecular and Cellular Bioscience [1050966] Funding Source: National Science Foundation
- Division Of Physics
- Direct For Mathematical & Physical Scien [1308264] Funding Source: National Science Foundation
- Div Of Molecular and Cellular Bioscience
- Direct For Biological Sciences [1214457] Funding Source: National Science Foundation
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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.
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