TY - JOUR
T1 - Accurate Methyl Group Dynamics in Protein Simulations with AMBER Force Fields
AU - Hoffmann, Falk
AU - Mulder, Frans A. A.
AU - Schaefer, Lars V.
PY - 2018/5/17
Y1 - 2018/5/17
N2 - An approach is presented to directly simulate the dynamics of methyl groups in protein side-chains, as accessible via NMR spin relaxation measurements, by all-atom MD simulations. The method, which does not rely on NMR information or any system-specific adjustable parameters, is based on calculating the time-correlation functions (TCFs) of the C-H bonds in methyl groups and explicitly takes the truncation of the TCFs due to overall tumbling of the molecule into account. Using ubiquitin as a model protein, we show (i) that an accurate description of the methyl dynamics requires reparametrization of the potential energy barriers of methyl group rotation in the AMBER ff99SB∗-ILDN force field (and related parameter sets), which was done with CCSD(T) coupled cluster calculations of isolated dipeptides as reference, and (ii) that the TIP4P/2005 solvation model yields overall tumbling correlation times that are in close agreement with experimental data. The methyl axis squared order parameters Saxis 2 and associated correlation times τ
f, obtained within the Lipari-Szabo formalism, are in good agreement with the values derived from NMR deuterium relaxation experiments. Importantly, the relaxation rates and spectral densities derived from MD and NMR agree as well, enabling a direct comparison without assumptions inherent to simplified motional models.
AB - An approach is presented to directly simulate the dynamics of methyl groups in protein side-chains, as accessible via NMR spin relaxation measurements, by all-atom MD simulations. The method, which does not rely on NMR information or any system-specific adjustable parameters, is based on calculating the time-correlation functions (TCFs) of the C-H bonds in methyl groups and explicitly takes the truncation of the TCFs due to overall tumbling of the molecule into account. Using ubiquitin as a model protein, we show (i) that an accurate description of the methyl dynamics requires reparametrization of the potential energy barriers of methyl group rotation in the AMBER ff99SB∗-ILDN force field (and related parameter sets), which was done with CCSD(T) coupled cluster calculations of isolated dipeptides as reference, and (ii) that the TIP4P/2005 solvation model yields overall tumbling correlation times that are in close agreement with experimental data. The methyl axis squared order parameters Saxis 2 and associated correlation times τ
f, obtained within the Lipari-Szabo formalism, are in good agreement with the values derived from NMR deuterium relaxation experiments. Importantly, the relaxation rates and spectral densities derived from MD and NMR agree as well, enabling a direct comparison without assumptions inherent to simplified motional models.
KW - SIDE-CHAIN DYNAMICS
KW - NMR RELAXATION DATA
KW - MAGNETIC-RESONANCE RELAXATION
KW - ORDER-PARAMETER ANALYSIS
KW - DEUTERIUM SPIN PROBES
KW - MODEL-FREE APPROACH
KW - MOLECULAR-DYNAMICS
KW - ROTATIONAL DIFFUSION
KW - CONFORMATIONAL ENTROPY
KW - COMPUTER-SIMULATION
UR - http://www.scopus.com/inward/record.url?scp=85046471474&partnerID=8YFLogxK
U2 - 10.1021/acs.jpcb.8b02769
DO - 10.1021/acs.jpcb.8b02769
M3 - Journal article
C2 - 29695158
SN - 1520-6106
VL - 122
SP - 5038
EP - 5048
JO - Journal of Physical Chemistry B
JF - Journal of Physical Chemistry B
IS - 19
ER -