Many of the early computer science approaches to protein folding were laughably naive, and the assumption about folding described in the Fraenkel paper: "It is believed that the native folded three-dimensional conformation of a protein is its lowest free energy state, or one of its lowest. "

is not factually correct. In reality, proteins never reach their lowest energy state unless they are very simple proteins, instead, they rapidly reach a state of kinetic interconversion between several accessible states. We can simulate proteins and measure those state transitions.

Really, solving protein folding is about classical approximations and clever sampling.