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Abstract
Protein folding is often viewed in terms of a funneled potential or free energy landscape. A variety of experiments now indicate the existence of multifunnel landscapes, associated with multifunctional biomolecules. Here, we present evidence that these systems have evolved to exhibit the minimal number of funnels required to fulfill their cellular functions, suggesting an extension to the principle of minimum frustration. We find that minimal disruptive mutations result in additional funnels, and the associated structural ensembles become more diverse. The same trends are observed in an atomic cluster. These observations suggest guidelines for rational design of engineered multifunctional biomolecules.
Highlights
The structure−function paradigm is the cornerstone of our understanding for biological processes at a molecular level
One theoretical framework to address this problem is provided by the potential energy landscape, which contains all of the information necessary to understand the molecular thermodynamic, kinetic, and structural properties
We have presented evidence that some specific biomolecules have evolved to exhibit the minimal number of funnels on their energy landscape to fulfill their functions
Summary
The structure−function paradigm is the cornerstone of our understanding for biological processes at a molecular level. Functional globular proteins appear to have evolved to reduce frustration as far as possible, and usually exhibit single-funneled landscapes based on a particular global minimum structural ensemble. In this case, a single funnel on the potential energy landscape can be used to define a single funnel on the free energy landscape for physiological temperatures of interest. Nelson and Onuchic[8] showed that minimal frustration in natural proteins leads to sequences that have evolved to support the native contacts in the global minimum structural ensemble, resulting in a deep funnel
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