How Fast-Folding Proteins Fold

TLDR

Understanding how proteins fold into their three-dimensional structures remains a major challenge in molecular biology. We used atomic‑level molecular dynamics simulations spanning 100 µs to 1 ms to uncover common principles of folding in 12 diverse proteins. Using a single physics‑based energy function, the simulations showed that proteins from all three structural classes spontaneously and repeatedly fold to their native structures. Early in folding, the backbone adopts a native‑like topology while certain secondary structures and a few nonlocal contacts form, and most proteins follow a single dominant route in which native elements appear in an order correlated with their propensity to form in the unfolded state.

Abstract

An outstanding challenge in the field of molecular biology has been to understand the process by which proteins fold into their characteristic three-dimensional structures. Here, we report the results of atomic-level molecular dynamics simulations, over periods ranging between 100 μs and 1 ms, that reveal a set of common principles underlying the folding of 12 structurally diverse proteins. In simulations conducted with a single physics-based energy function, the proteins, representing all three major structural classes, spontaneously and repeatedly fold to their experimentally determined native structures. Early in the folding process, the protein backbone adopts a nativelike topology while certain secondary structure elements and a small number of nonlocal contacts form. In most cases, folding follows a single dominant route in which elements of the native structure appear in an order highly correlated with their propensity to form in the unfolded state.