10.1021/ja0687668.s001
Phineus R. L. Markwick
Phineus
R. L. Markwick
Guillaume Bouvignies
Guillaume
Bouvignies
Martin Blackledge
Martin
Blackledge
Exploring Multiple Timescale Motions in Protein GB3 Using
Accelerated Molecular Dynamics and NMR Spectroscopy
American Chemical Society
2007
dynamic
Molecular Dynamics
Protein GB 3
mode
solvated MD simulations
AMD
NMR SpectroscopyBiological function
Exploring Multiple Timescale Motions
substate
amplitude
15 N relaxation
protein
order parameters
2007-04-18 00:00:00
Journal contribution
https://acs.figshare.com/articles/journal_contribution/Exploring_Multiple_Timescale_Motions_in_Protein_GB3_Using_Accelerated_Molecular_Dynamics_and_NMR_Spectroscopy/3011950
Biological function relies on the complex spectrum of conformational dynamics occurring in
biomolecules. We have combined Accelerated Molecular Dynamics (AMD) with experimental results derived
from NMR to probe multiple time-scale motions in the third IgG-binding domain of Protein G (GB3). AMD
is shown to accurately reproduce the amplitude and distribution of slow motional modes characterized
using residual dipolar couplings, reporting on dynamics up to the millisecond timescale. In agreement with
experiment, larger amplitude slower motions are localized in the β-strand/loop motif spanning residues
14−24 and in loop 42−44. Principal component analysis shows these fluctuations participating in the primary
mode, substantiating the existence of a correlated motion traversing the β-sheet that culminates in maximum
excursions at the active site of the molecule. Fast dynamics were simulated using extensive standard MD
simulations and compared to order parameters extracted from <sup>15</sup>N relaxation. Notably 60 2-ns fully solvated
MD simulations exploring the different conformational substates sampled from AMD resulted in better
reproduction of order parameters compared to the same number of simulations starting from the relaxed
crystal structure. This illustrates the inherent dependence of protein dynamics on local conformational
topology. The results provide rare insight into the complex hierarchy of dynamics present in GB3 and allow
us to develop a model of the conformational landscape native to the protein, appearing as a steep sided
potential well whose flat bottom comprises multiple similar but discrete conformational substates.