Bernhard Egwolf
University of Chicago
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Featured researches published by Bernhard Egwolf.
The Journal of General Physiology | 2011
Benoît Roux; Simon Bernèche; Bernhard Egwolf; Bogdan Lev; Sergei Y. Noskov; Christopher N. Rowley; Haibo Yu
A multitude of biological processes requires the participation of specific cations, such as H+, Na+, K+, Ca2+, and Mg2+. Many of these processes can take place only when proteins have the ability to discriminate between different ions with a very high fidelity. How this is possible is a fundamental
Journal of Chemical Physics | 2003
Gerald Mathias; Bernhard Egwolf; Marco Nonella; Paul Tavan
We present a combination of the structure adapted multipole method with a reaction field (RF) correction for the efficient evaluation of electrostatic interactions in molecular dynamics simulations under periodic boundary conditions. The algorithm switches from an explicit electrostatics evaluation to a continuum description at the maximal distance that is consistent with the minimum image convention, and, thus, avoids the use of a periodic electrostatic potential. A physically motivated switching function enables charge clusters interacting with a given charge to smoothly move into the solvent continuum by passing through the spherical dielectric boundary surrounding this charge. This transition is complete as soon as the cluster has reached the so-called truncation radius Rc. The algorithm is used to examine the dependence of thermodynamic properties and correlation functions on Rc in the three point transferable intermolecular potential water model. Our test simulations on pure liquid water used either...
Journal of Molecular Biology | 2010
Bernhard Egwolf; Benoît Roux
Potassium (K(+)) channels are specialized membrane proteins that are able to facilitate and regulate the conduction of K(+) through cell membranes. Comprising five specific cation binding sites (S(0)-S(4)) formed by the backbone carbonyl groups of conserved residues common to all K(+) channels, the narrow selectivity filter allows fast conduction of K(+) while being highly selective for K(+) over Na(+). To extend our knowledge of the microscopic mechanism underlying selectivity in K(+) channels, we characterize the free energy landscapes governing the entry and translocation of a Na(+) or a K(+) from the extracellular side into the selectivity filter of KcsA. The entry process of an extracellular ion is examined in the presence of two additional K(+) in the pore, and the three-ion potential of mean force is computed using extensive all-atom umbrella sampling molecular dynamics simulations. A comparison of the potentials of mean force yields a number of important results. First, the free energy minima corresponding to configurations with extracellular K(+) or Na(+) in binding site S(0) or S(1) are similar in depth, suggesting that the thermodynamic selectivity governed by the free energy minima for those two binding sites is insignificant. Second, the free energy barriers between stable multi-ion configurations are generally higher for Na(+) than for K(+), implying that the kinetics of ion conduction is slower when a Na(+) enters the pore. Third, the region corresponding to binding site S(2) near the center of the narrow pore emerges as the most selective for K(+) over Na(+). In particular, while there is a stable minimum for K(+) in site S(2), Na(+) faces a steep free energy increase with no local free energy well in this region. Lastly, analysis shows that selectivity is not correlated with the overall coordination number of the ion entering the pore, but is predominantly affected by changes in the type of coordinating ligands (carbonyls versus water molecules). These results further highlight the importance of the central region near binding site S(2) in the selectivity filter of K(+) channels.
Journal of Computational Chemistry | 2012
Kyu Il Lee; Sunhwan Jo; Huan Rui; Bernhard Egwolf; Benoît Roux; Richard W. Pastor; Wonpil Im
Brownian dynamics (BD) based on accurate potential of mean force is an efficient and accurate method for simulating ion transport through wide ion channels. Here, a web‐based graphical user interface (GUI) is presented for carrying out grand canonical Monte Carlo (GCMC) BD simulations of channel proteins: http://www.charmm‐gui.org/input/gcmcbd. The webserver is designed to help users avoid most of the technical difficulties and issues encountered in setting up and simulating complex pore systems. GCMC/BD simulation results for three proteins, the voltage dependent anion channel (VDAC), α‐Hemolysin (α‐HL), and the protective antigen pore of the anthrax toxin (PA), are presented to illustrate the system setup, input preparation, and typical output (conductance, ion density profile, ion selectivity, and ion asymmetry). Two models for the input diffusion constants for potassium and chloride ions in the pore are compared: scaling of the bulk diffusion constants by 0.5, as deduced from previous all‐atom molecular dynamics simulations of VDAC, and a hydrodynamics based model (HD) of diffusion through a tube. The HD model yields excellent agreement with experimental conductances for VDAC and α‐HL, while scaling bulk diffusion constants by 0.5 leads to underestimates of 10–20%. For PA, simulated ion conduction values overestimate experimental values by a factor of 1.5–7 (depending on His protonation state and the transmembrane potential), implying that the currently available computational model of this protein requires further structural refinement.
Journal of Biological Chemistry | 2011
Walter Sandtner; Bernhard Egwolf; Fatemeh Khalili-Araghi; Jorge E. Sánchez-Rodríguez; Benoît Roux; Francisco Bezanilla; Miguel Holmgren
Background: Ouabain binds at the permeation pathway of the Na+/K+ ATPase. Results: We have identified two binding sites for ouabain along the ion conductive pathway of the Na+/K+ pump that are mutually exclusive and differ in their affinities by about an order of magnitude. Conclusion: Ouabain reaches its high affinity binding site at the inner end of the permeation pathway by a sequential mechanism. Significance: This work unifies all available functional and structural data on the interactions of ouabain with the Na+/K+ pump. The Na+/K+ ATPase is an almost ubiquitous integral membrane protein within the animal kingdom. It is also the selective target for cardiotonic derivatives, widely prescribed inhibitors for patients with heart failure. Functional studies revealed that ouabain-sensitive residues distributed widely throughout the primary sequence of the protein. Recently, structural work has brought some consensus to the functional observations. Here, we use a spectroscopic approach to estimate distances between a fluorescent ouabain and a lanthanide binding tag (LBT), which was introduced at five different positions in the Na+/K+ ATPase sequence. These five normally functional LBT-Na+/K+ ATPase constructs were expressed in the cell membrane of Xenopus laevis oocytes, operating under physiological internal and external ion conditions. The spectroscopic data suggest two mutually exclusive distances between the LBT and the fluorescent ouabain. From the estimated distances and using homology models of the LBT-Na+/K+ ATPase constructs, approximate ouabain positions could be determined. Our results suggest that ouabain binds at two sites along the ion permeation pathway of the Na+/K+ ATPase. The external site (low apparent affinity) occupies the same region as previous structural findings. The high apparent affinity site is, however, slightly deeper toward the intracellular end of the protein. Interestingly, in both cases the lactone ring faces outward. We propose a sequential ouabain binding mechanism that is consistent with all functional and structural studies.
Journal of Physical Chemistry B | 2010
Yun Luo; Bernhard Egwolf; D. Eric Walters; Benoı̂t Roux
The alpha-hemolysin (alphaHL) is a self-assembling exotoxin that binds to the membrane of a susceptible host cell and causes its death. Experimental studies show that electrically neutral beta-cyclodextrin (betaCD) can insert into the alphaHL channel and significantly increase its anion selectivity. To understand how betaCD can affect ion selectivity, molecular dynamics simulations and potential of mean force (PMF) calculations are carried out for different alphaHL channels with and without the betaCD adapter. A multiscale approach based on the generalized solvent boundary potential is used to reduce the size of the simulated system. The PMF profiles reveal that betaCD has no anion selectivity by itself but can increase the Cl(-) selectivity of the alphaHL channel when lodged into the pore lumen. Analysis shows that betaCD causes a partial desolvation of ions and affects the orientation of nearby charged residues. The ion selectivity appears to result from increased electrostatic interaction between the ion and the channel due to a reduction in dielectric shielding by the solvent. These observations suggest a reasonable explanation of the ion selectivity and provide important information for further ion channel modification.
Journal of Chemical Physics | 2003
Bernhard Egwolf; Paul Tavan
We present a continuum approach for efficient and accurate calculation of reaction field forces and energies in classical molecular-dynamics (MD) simulations of proteins in water. The derivation proceeds in two steps. First, we reformulate the electrostatics of an arbitrarily shaped molecular system, which contains partially charged atoms and is embedded in a dielectric continuum representing the water. A so-called fuzzy partition is used to exactly decompose the system into partial atomic volumes. The reaction field is expressed by means of dipole densities localized at the atoms. Since these densities cannot be calculated analytically for general systems, we introduce and carefully analyze a set of approximations in a second step. These approximations allow us to represent the dipole densities by simple dipoles localized at the atoms. We derive a system of linear equations for these dipoles, which can be solved numerically by iteration. After determining the two free parameters of our approximate method...
Journal of Chemical Physics | 2004
Bernhard Egwolf; Paul Tavan
We extend our continuum description of solvent dielectrics in molecular-dynamics (MD) simulations, which has provided an efficient and accurate solution of the Poisson equation, to ionic solvents as described by the linearized Poisson-Boltzmann (LPB) equation. We start with the formulation of a general theory for the electrostatics of an arbitrarily shaped molecular system, which consists of partially charged atoms and is embedded in a LPB continuum. This theory represents the reaction field induced by the continuum in terms of charge and dipole densities localized within the molecular system. Because these densities cannot be calculated analytically for systems of arbitrary shape, we introduce an atom-based discretization and a set of carefully designed approximations. This allows us to represent the densities by charges and dipoles located at the atoms. Coupled systems of linear equations determine these multipoles and can be rapidly solved by iteration during a MD simulation. The multipoles yield the reaction field forces and energies. Finally, we scrutinize the quality of our approach by comparisons with an analytical solution restricted to perfectly spherical systems and with results of a finite difference method.
Journal of Physical Chemistry B | 2010
Bernhard Egwolf; Yun Luo; D. Eric Walters; Benoı̂t Roux
Biophysical Journal | 2012
Walter Sandtner; Bernhard Egwolf; Fatemeh Khalili-Araghi; Jorge E. Sánchez-Rodríguez; Benoît Roux; Francisco Bezanilla; Miguel Holmgren