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Oral 06
Abstract
TRANSIENT ACCESS TO THE PROTEIN INTERIOR:
MAGNETIC RELAXATION DISPERSION VERSUS SIMULATION
Filip Persson <strong>and</strong> Bertil Halle
Dept of Biophysical Chemistry, Lund University, SE-22100 Lund, Sweden
Many proteins rely for their function on rare structural fluctuations whereby solvent <strong>and</strong> other
small molecules gain transient access to internal cavities. In magnetic relaxation dispersion
(MRD) experiments, water molecules buried in such cavities can be used as intrinsic probes
of the intermittent protein motions that govern their exchange with external solvent. While
this has allowed a detailed characterization of exchange kinetics for several proteins, 1 little is
known about the exchange mechanism. Here, 2 we use a millisecond all-atom MD trajectory 3
to characterize water exchange from the four internal hydration sites in the protein BPTI.
Using a recently developed stochastic point process approach, 4 we compute the survival
correlation function probed by MRD experiments as well as other quantities designed to
validate the exchange-mediated orientational r<strong>and</strong>omization (EMOR) model used to interpret
the MRD data. The EMOR model is found to be quantitatively accurate <strong>and</strong> the simulation
reproduces the experimental mean survival times for all four sites with activation energy
discrepancies in the range 0 – 3 k B T. On the other h<strong>and</strong>, the simulated hydration sites are
somewhat too flexible <strong>and</strong> the water flip barrier is underestimated by up to 6 k B T. The
simulation reveals that water molecules gain access to the internal sites by a transient
aqueduct mechanism, where single-file water chains migrate through transient (< 5 ns)
tunnels <strong>and</strong> pores (see MD snapshot below).
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1 E Persson & B Halle, J Am Chem Soc 130, 1774 (2008).
2 F Persson & B Halle, J Am Chem Soc, in press.
3 DE Shaw et al., Science 330, 341 (2010).
4 B Halle & F Persson, J Chem Theory Comput, in press.
<strong>8th</strong> <strong>Conference</strong> on Fast Field Cycling NMR Relaxometry, Turin 23-25 May 2013