Protein Folding Funnel

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The above diagram sketches one possible explanation for how proteins fold into their native structures that is based on the physics concept of minimizing free energy. In this model, the unfolded protein had both high entropy and high free energy. The high entropy corresponds to there being a large number of possible conformational states—the molecule can take on many different three-dimensional shapes. The high free energy means that the molecule is unstable, and flops easily between the different conformational states. As the protein starts to fold, the free energy drops and the number of available conformational states (denoted by the width of the funnel) decreases. There are local minima along the way that can trap the protein in a metastable state for some time, slowing its progress towards the free energy minimum. At the bottom of the funnel, the free energy is at a minimum and there is only one conformational state available to the protein molecule. This is called its native state, and is the ground state of the system. It is possible that the native state is not unique—there can be several states with approximately equal free energy at the bottom of the funnel. (Unit: 9)