Calculation of Protein Folding Thermodynamics Using Molecular Dynamics Simulations.

Despite advances in artificial intelligence methods, protein folding remains in many ways an enigma to be solved. Accurate computation of protein folding energetics could help drive fields such as protein and drug design and genetic interpretation. However, the challenge of calculating the state functions governing protein folding from first-principles remains unaddressed. We present here a simple approach that allows us to accurately calculate the energetics of protein folding. It is based on computing the energy of the folded and unfolded states at different temperatures using molecular dynamics simulations. From this, two essential quantities (Δ H and ΔCp) are obtained and used to calculate the conformational stability of the protein (Δ G ). With this approach, we have successfully calculated the energetics of two- and three-state proteins, representatives of the major structural classes, as well as small stability differences (ΔΔ G ) due to changes in solution conditions or variations in an amino acid residue.