Understanding protein unfolding from molecular simulations

Experimental biophysical techniques can probe the native, transition, intermediate, and denatured states of proteins. The characterization of these states and the conversion between states provide us with information about folding, dynamics, misfolding, and the origin of mechanical strength in response to force. Molecular dynamics (MD) simulations are a complementary theoretical technique that provides atomic detail to the experimental measurements particularly through careful benchmarking and validation against experiment. Furthermore, MD simulations often correctly predict the outcome of experiments and provide new and interesting avenues of investigation. Our understanding of protein unfolding is being pushed forward by the symbiosis of experimental and theoretical methods. Here, we review investigations of several protein systems and highlight the close interplay between experiment and simulation in providing an atomic resolution view of protein unfolding, which provide us with the general principles for folding and the origin of mechanical strength.