title: Thermal denaturing of mutant lysozyme with both the OPLSAA and the CHARMM force fields.
abstract: Biomolecular simulations enabled by massively parallel supercomputers such as BlueGene/L promise to bridge the gap between the currently accessible simulation time scale and the experimental time scale for many important protein folding processes. In this study, molecular dynamics simulations were carried out for both the wild-type and the mutant hen lysozyme (TRP62GLY) to study the single mutation effect on lysozyme stability and misfolding. Our thermal denaturing simulations at 400-500 K with both the OPLSAA and the CHARMM force fields show that the mutant structure is indeed much less stable than the wild-type, which is consistent with the recent urea denaturing experiment (Dobson et al. Science 2002, 295, 1719-1722; Nature 2003, 424, 783-788). Detailed results also reveal that the single mutation TRP62GLY first induces the loss of native contacts in the beta-domain region of the lysozyme protein at high temperatures, and then the unfolding process spreads into the alpha-domain region through Helix C. Even though the OPLSAA force field in general shows a more stable protein structure than does the CHARMM force field at high temperatures, the two force fields examined here display qualitatively similar results for the misfolding process, indicating that the thermal denaturing of the single mutation is robust and reproducible with various modern force fields.
authors.affiliation: Computational Biology Center, Deep Computing Institute, IBM Watson Research Center, Yorktown Heights, NY 10598, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Eleftheriou
authors.forename: Robert S
authors.initials: RS
authors.lastname: Germain
authors.forename: Ajay K
authors.initials: AK
authors.lastname: Royyuru
authors.forename: Ruhong
authors.initials: R
authors.lastname: Zhou
mesh_terms: D000818:Animals; D002645:Chickens; D003198:Computer Simulation; D004735:Energy Transfer; D005998:Glycine / Q000235:genetics; D006358:Hot Temperature; D009113:Muramidase / Q000737:chemistry* / Q000235:genetics; D009154:Mutation; D011489:Protein Denaturation; D017433:Protein Structure, Secondary; D013057:Spectrum Analysis; D055672:Static Electricity; D013997:Time Factors; D014364:Tryptophan / Q000235:genetics
chemical_list: D014364:Tryptophan; D009113:Muramidase; D005998:Glycine