RT Journal Article
SR Electronic
T1 Molecular Interactions and Forces that Make Proteins Stable: A Quantitative Inventory from Atomistic Molecular Dynamics Simulations
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2023.01.23.525230
DO 10.1101/2023.01.23.525230
A1 Juan José Galano-Frutos
A1 Javier Sancho
YR 2023
UL http://biorxiv.org/content/early/2023/01/23/2023.01.23.525230.abstract
AB Protein design requires a deep control of protein folding energetics, which can be determined experimentally on a case-by-case basis but is not understood in sufficient detail. Calorimetry, protein engineering and biophysical modeling have outlined the fundamentals of protein stability, but these approaches face difficulties in elucidating the specific contributions of the intervening molecules and elementary interactions to the folding energy balance. Recently, we showed that, using Molecular Dynamics (MD) simulations of native proteins and their unfolded ensembles, one can calculate, within experimental error, the enthalpy and heat capacity changes of the folding reaction. Analyzing MD simulations of four model proteins (CI2, barnase, SNase and apoflavodoxin) whose folding enthalpy and heat capacity changes have been successfully calculated, we dissect here the energetic contributions to protein stability made by the different molecular players (polypeptide and solvent molecules) and elementary interactions (electrostatic, van der Waals and bonded) involved. Although the proteins analyzed differ in length (65-168 amino acid residues), isoelectric point (4.0-8.99) and overall fold, their folding energetics is governed by the same quantitative pattern. Relative to the unfolded ensemble, the native conformation is enthalpically stabilized by comparable contributions from protein-protein and solvent-solvent interactions, and it is nearly equally destabilized by interactions between protein and solvent molecules. From the perspective of elementary physical interactions, the native conformation is stabilized by van de Waals and coulombic interactions and is destabilized by bonded interactions. Also common to the four proteins, the sign of the heat capacity change is set by protein-solvent interactions or, from the alternative perspective, by coulombic interactions.Competing Interest StatementThe authors have declared no competing interest.ISIonic StrengthLNLennard-JonesMDMolecular DynamicsNMRNuclear Magnetic ResonanceNNNon-protein-Non-proteinPPProtein-ProteinPNProtein-Non-proteinRgRadius of gyrationSASASolvent-Accessible Surface AreaSAXSSmall-Angle X-ray Scattering