In this context, what are macrostates?
• The entropy, enthalpy and energy we have discussed so far are properties of macrostates (e.g. the native state, unfolded state)
• Macrostates consist of an ensemble of microstates: the individual conformations

The free energy components of a microstate (A) can be expressed in terms of the probabilities of the microstates (i) in that macrostate
What is meant by ensemble average?
• A macrostate is not a single conformation, it consists of an collection of conformations
• To describe the properties of a macrostate (A), we typically calculate an ensemble average
What kind of experimental values can be measured that you expect to be different between the folded and the unfolded state?
• N-C distance
• Total hydrophobic surface area
• Enzymatic activity
• Hydrogen bonds
• Fluorescence (e.g. FRET)
How can the free energy difference between two states be calculated?
The free energy difference between two states can be calculated from the ratio of their probabilities.
What would happen if visited all possible states were visited?
• Imagine a 100-residue protein where the φ-and ψ-angles can only have 3 values →3200≈ 1095possible structures
• Assume 10 ps(10-11 s) per structure
• To visit all states, this would take ~ 1076 years

• Number of relevant non-folded structures is much smaller than the number of possible non-folded structures
• If the number of relevant non-folded structures increases proportionally with the folding time, only 109 protein structures need to be simulated instead of 1095 structures
• So perhaps simpler after all...
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