TY - JOUR
T1 - Imaging α-hemolysin with molecular dynamics
T2 - Ionic conductance, osmotic permeability, and the electrostatic potential map
AU - Aksimentiev, Aleksij
AU - Schulten, Klaus
N1 - This work was supported by grants from the National Institutes of Health (PHS 5 P41 RR05969 and 1 R01 GM067887). The authors gratefully acknowledge supercomputer time provided by the Pittsburgh Supercomputer Center and the National Center for Supercomputing Applications via National Resources Allocation Committee grant MCA93S028.
PY - 2005/6
Y1 - 2005/6
N2 - α-Hemolysin of Staphyiococcus aureus is a self-assembling toxin that forms a water-filled transmembrane channel upon oligomerization in a lipid membrane. Apart from being one of the best-studied toxins of bacterial origin, α-hemolysin is the principal component in several biotechnological applications, including systems for controlled delivery of small solutes across lipid membranes, stochastic sensors for small solutes, and an alternative to conventional technology for DN A sequencing. Through large-scale molecular dynamics simulations, we studied the permeability of the α-hemolysin/lipid bilayer complex for water and ions. The studied system, composed of -300,000 atoms, included one copy of the protein, a patch of a DPPC lipid bilayer, and a 1 M water solution of KCl. Monitoring the fluctuations of the pore structure revealed an asymmetric, on average, cross section of the α-hemolysin stem. Applying external electrostatic fields produced a transmembrane ionic current; repeating simulations at several voltage biases yielded a current/voltage curve of α-hemolysin and a set of electrostatic potential maps. The selectivity of α-hemolysin to Cl- was found to depend on the direction and the magnitude of the applied voltage bias. The results of our simulations are in excellent quantitative agreement with available experimental data. Analyzing trajectories of all water molecule, we computed the α-hemolysin's osmotic permeability for water as well as its electroosmotic effect, and characterized the permeability of its seven side channels. The side channels were found to connect seven His-144 residues surrounding the stem of the protein to the bulk solution; the protonation of these residues was observed to affect the ion conductance, suggesting the seven His-144 to comprise the pH sensor that gates conductance of the α-hemolysin channel.
AB - α-Hemolysin of Staphyiococcus aureus is a self-assembling toxin that forms a water-filled transmembrane channel upon oligomerization in a lipid membrane. Apart from being one of the best-studied toxins of bacterial origin, α-hemolysin is the principal component in several biotechnological applications, including systems for controlled delivery of small solutes across lipid membranes, stochastic sensors for small solutes, and an alternative to conventional technology for DN A sequencing. Through large-scale molecular dynamics simulations, we studied the permeability of the α-hemolysin/lipid bilayer complex for water and ions. The studied system, composed of -300,000 atoms, included one copy of the protein, a patch of a DPPC lipid bilayer, and a 1 M water solution of KCl. Monitoring the fluctuations of the pore structure revealed an asymmetric, on average, cross section of the α-hemolysin stem. Applying external electrostatic fields produced a transmembrane ionic current; repeating simulations at several voltage biases yielded a current/voltage curve of α-hemolysin and a set of electrostatic potential maps. The selectivity of α-hemolysin to Cl- was found to depend on the direction and the magnitude of the applied voltage bias. The results of our simulations are in excellent quantitative agreement with available experimental data. Analyzing trajectories of all water molecule, we computed the α-hemolysin's osmotic permeability for water as well as its electroosmotic effect, and characterized the permeability of its seven side channels. The side channels were found to connect seven His-144 residues surrounding the stem of the protein to the bulk solution; the protonation of these residues was observed to affect the ion conductance, suggesting the seven His-144 to comprise the pH sensor that gates conductance of the α-hemolysin channel.
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U2 - 10.1529/biophysj.104.058727
DO - 10.1529/biophysj.104.058727
M3 - Article
C2 - 15764651
AN - SCOPUS:22244445788
SN - 0006-3495
VL - 88
SP - 3745
EP - 3761
JO - Biophysical journal
JF - Biophysical journal
IS - 6
ER -