期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 111, 期 30, 页码 11031-11036出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1410529111
关键词
energy landscape theory; molecular dynamics
资金
- National Institute of General Medical Sciences [R01 GM44557, P01 GM071862]
- Center for Theoretical Biological Physics - National Science Foundation (NSF) [PHY-0822283]
- Data Analysis and Visualization Cyberinfrastructure - NSF [OCI-0959097]
- Division Of Physics
- Direct For Mathematical & Physical Scien [1427654] Funding Source: National Science Foundation
We explore the hypothesis that the folding landscapes of membrane proteins are funneled once the proteins' topology within the membrane is established. We extend a protein folding model, the associative memory, water-mediated, structure, and energy model (AWSEM) by adding an implicit membrane potential and reoptimizing the force field to account for the differing nature of the interactions that stabilize proteins within lipid membranes, yielding a model that we call AWSEM-membrane. Once the protein topology is set in the membrane, hydrophobic attractions play a lesser role in finding the native structure, whereas polar-polar attractions are more important than for globular proteins. We examine both the quality of predictions made with AWSEM-membrane when accurate knowledge of the topology and secondary structure is available and the quality of predictions made without such knowledge, instead using bioinformatically inferred topology and secondary structure based on sequence alone. When no major errors are made by the bioinformatic methods used to assign the topology of the transmembrane helices, these two types of structure predictions yield roughly equivalent quality structures. Although the predictive energy landscape is transferable and not structure based, within the correct topological sector we find the landscape is indeed very funneled: Thermodynamic landscape analysis indicates that both the total potential energy and the contact energy decrease as native contacts are formed. Nevertheless the near symmetry of different helical packings with respect to native contact formation can result in multiple packings with nearly equal thermodynamic occupancy, especially at temperatures just below collapse.
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