Prediction of protein relative enthalpic stability from molecular dynamics simulations of the folded and unfolded states.
For proteins of known structure, the relative enthalpic stability with respect to wild-type, ΔΔH(U), can be estimated by direct computation of the folded and unfolded state energies. We propose a model by which the change in stability upon mutation can be predicted from all-atom molecular dynamics simulations for the folded state and a peptide-based model for the unfolded state. The unfolding enthalpies are expressed in terms of environmental and hydration-solvent reorganization contributions that readily allow a residue-specific analysis of ΔΔH(U). The method is applied to estimate the relative enthalpic stability of variants with buried charged groups in T4 lysozyme. The predicted relative stabilities are in good agreement with experimental data. Environmental factors are observed to contribute more than hydration to the overall ΔΔH(U). The residue-specific analysis finds that the effects of burying charge are both localized and long-range. The enthalpy for hydration-solvent reorganization varies considerably among different amino-acid types, but because the variant folded state structures are similar to those of the wild-type, the hydration-solvent reorganization contribution to ΔΔH(U) is localized at the mutation site, in contrast to environmental contributions. Overall, mutation of apolar and polar amino acids to charged amino acids are destabilizing, but the reasons are complex and differ from site to site.
Markey Center for Structural Biology, Department of Medicinal Chemistry, Purdue University, West Lafayette, Indiana, USA.
Voichita M
VM
Dadarlat
Lev A
LA
Gorenstein
Carol Beth
CB
Post
D000595:Amino Acid Sequence; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D009113:Muramidase / Q000737:chemistry* / Q000235:genetics; D009154:Mutation; D017510:Protein Folding; D055550:Protein Stability; D055672:Static Electricity
D009113:Muramidase