Date of Completion
Eric R. May; Peter Schweitzer
Analytical Chemistry | Biological and Chemical Physics | Biophysics | Molecular Biology | Other Biochemistry, Biophysics, and Structural Biology | Structural Biology
Among structural biology techniques, Nuclear Magnetic Resonance (NMR) provides a holistic view of structure that is close to protein structure in situ. Namely, NMR imaging allows for the solution state of the protein to be observed, derived from Nuclear Overhauser Effect restraints (NOEs). NOEs are a distance range in which hydrogen pairs are observed to stay within range of, and therefore experimental data which computational models can be compared against. To that end, we investigated the effects of adding the NOE restraints as distance restraints in Molecular Dynamics (MD) simulations on the 24 residue HP24stab derived villin headpiece subdomain to find the most optimal restraint level. Previous work in the May Lab examined implementing NOE restraints on Szeto-Schiller (SS) peptides, and found that implementing NOEs played a key role in shifting the ensemble of SS peptides conformations to more closely reflect NMR solved structures. Our analysis includes a larger focus on overall protein stability through root-mean-squared-deviation (RMSD) analysis in addition to time-averaging analysis of direct NOE violations themselves. Moreover, the study also explores possible differences in impact that NOEs can have on simulations using different molecular mechanics force fields: CHARMM36 and Amber19SB. The results indication that modulating restraint levels bears a greater influence on Amber19SB simulated protein stability than CHARMM36, however adding NOE restraints did not necessarily result in improved accuracy of the MD simulations.
Patel, Milan, "Modeling Accuracy Matters: Aligning Molecular Dynamics with 2D NMR Derived NOE Restraints" (2023). Honors Scholar Theses. 958.