DR. BENOIT ROUX, 2017 BSC FELLOW
Dr. Roux’s studies provide a computational roadmap toward an understanding of biological systems.
Dr. Benoît Roux received his B.Sc. and M.Sc. from the Université de Montréal in 1981 and 1984, respectively. He received his Ph.D. from Harvard University in 1990, working under the supervision of Dr. Martin Karplus. He is currently Professor of Biomedical Sciences at the University of Chicago.
Benoît Roux's theoretical and computational studies provide a roadmap on how to advance our understanding of biological systems using detailed computation. A unique quality to his work is conferred by its clarity, formal elegance, and rigor. At an early career stage he helped to clarify the fundamental relation between continuum electrostatic models and explicit molecular representations (Roux et al, 1990; Nina et al, 1997). He also established the first rigorous statistical mechanical formulation of hybrid explicit/implicit simulation approaches (Beglov and Roux, 1994; Im et al, 2001), and spawned simulation methodologies for calculating the absolute binding free energy of ligands to macromolecules (Roux et al, 1996; Woo and Roux, 2005; Deng and Roux, 2006; Gumbart et al, 2013).
His most significant and highly recognized work has established the physical principles that govern the function of the physiologically critical ion channels and integral membrane proteins, largely through his highly creative molecular dynamics simulations of biomembranes. He initiated these two decades ago in studies of the gramicidin channel, leading to the first molecular dynamics simulation of any protein embedded in an explicit phospholipid bilayer membrane (Woolf and Roux, 1994), and the prediction of its main binding sites (Roux and Karplus, 1993; Woolf and Roux, 1997).
The determination of the structure of the KcsA potassium channel Doyle et al (1998) provided the opportunity to extend and apply his methods to the much more challenging problem of a biologically-selective channel. His simulations showed that the water-filled vestibular cavity at the intracellular entrance of the KcsA channel achieved its selectivity for monovalent cations from an unusual and unexpected balance of the electrostatic reaction field (Roux and MacKinnon, 1999). He went on to show that the driving force for ion flux arising from the membrane potential is focused along the narrow pore (Roux et al, 2000). His ensuing studies included the computation of the multi-ion free energy landscape to explain the atomic basis of the knock-on mechanism of ion conduction proposed decades earlier by Hodgkin and Keynes (1955). They culminated in his prediction of the five main cation binding sites along the selectivity filter of the KcsA potassium channel (Berneche and Roux, 2001) that were then observed independently and experimentally in high resolution crystallographic structures (Zhou et al, 2001). He then used a computational approach to challenge the traditional and widely-held view that ion selectivity is derived from nearly rigid binding sites (Noskov et al, 2004; Yu et al, 2010). He showed that in contrast to this view, selectivity in the KcsA channel is controlled by the properties of the flexible carbonyl ligands that line the walls of the channel. In short, flexibility is central to selectivity. This work on ion selectivity in membrane transporters (Noskov and Roux, 2008; Yu et al, 2011) has fundamentally altered how the community thinks about the molecular determinants of ion selectivity, as evidenced by its incorporation in notable textbooks such as "Cell Biology" by Thomas D. Pollard.
After showing how the transmembrane potential can be rigorously incorporated into simulations (Roux, 1997; Roux, 2008), he deployed this approach to calculate the gating charge of the voltage-activated potassium channel and thus provide a unique, molecular-level insight into the voltage-dependent gating mechanism (Chanda et al, 2005; Pathak et al, 2007; Khalili et al, 2010; Li et al, 2014). His statistical mechanical theory of the membrane potential (Roux, 2008) has now become a standard molecular dynamics tool, widely adopted by other computational groups to calculated the gating charge of atomic models (e.g. see Grabe et al, 2005; Jensen et al, 2012).
Beglov, D., and B. Roux. 1994. Finite Representation of an Infinite Bulk System - Solvent Boundary Potential for Computer Simulations. Journal of Chemical Physics. 100:9050-9063.
Bernèche, S., and B. Roux. 2001. Energetics of ion conduction through the K+ channel. Nature. 414:73-77.
Chanda, B., O.K. Asamoah, R. Blunck, B. Roux, and F. Bezanilla. 2005. Gating charge displacement in voltage-gated ion channels involves limited transmembrane movement. Nature. 436:852-856.
Deng, Y.Q., and B. Roux. 2006. Calculation of standard binding free energies: Aromatic molecules in the T4 lysozyme L99A mutant. Journal of Chemical Theory and Computation. 2:1255-1273.
Doyle, D.A., J. Morais Cabral, R.A. Pfuetzner, A. Kuo, J.M. Gulbis, S.L. Cohen, B.T. Chait, and R. MacKinnon. 1998. The structure of the potassium channel: molecular basis of K+ conduction and selectivity. Science. 280:69-77.
Grabe, M., H. Lecar, Y.N. Jan, and L.Y. Jan. 2004. A quantitative assessment of models for voltage-dependent gating of ion channels. Proceedings of the National Academy of Sciences of the United States of America. 101:17640-17645.
Gumbart, J.C., B. Roux, and C. Chipot. 2013. Efficient Determination of Protein–Protein Standard Binding Free Energies from First Principles. J. Chem. Theo. Comp. 9:3789–3798.
Hodgkin, A.L., and R.D. Keynes. 1955. The potassium permeability of a giant nerve fibre. J. Physiol. (Lond.). 128:61-88.
Im, W., S. Bernèche, and B. Roux. 2001. Generalized solvent boundary potential for computer simulations. Journal of Chemical Physics. 114:2924-2937.
Jensen, M.O., V. Jogini, D.W. Borhani, A.E. Leffler, R.O. Dror, and D.E. Shaw. 2012. Mechanism of voltage gating in potassium channels. Science. 336:229-233.
Li, Q., S. Wanderling, M. Paduch, D. Medovoy, A. Singharoy, R. McGreevy, C.A. Villalba-Galea, R.E. Hulse, B. Roux, K. Schulten, A. Kossiakoff, and E. Perozo. 2014. Structural mechanism of voltage-dependent gating in an isolated voltage-sensing domain. Nat Struct Mol Biol. 21:244-252.
Nina, M., D. Beglov, and B. Roux. 1997. Atomic radii for continuum electrostatics calculations based on molecular dynamics free energy simulations. Journal of Physical Chemistry B. 101:5239-5248.
Noskov, S.Y., S. Bernèche, and B. Roux. 2004. Control of ion selectivity in potassium channels by electrostatic and dynamic properties of carbonyl ligands. Nature. 431:830-834.
Pathak, M.M., V. Yarov-Yarovoy, G. Agarwal, B. Roux, P. Barth, S. Kohout, F. Tombola, and E.Y. Isacoff. 2007. Closing in on the resting state of the shaker K+ channel. Neuron. 56:124-140.
Roux, B. 1997. Influence of the membrane potential on the free energy of an intrinsic protein. Biophysical Journal. 73:2980-2989.
Roux, B. 2008. The membrane potential and its representation by a constant electric field in computer simulations. Biophys J. 95:4205-4216.
Roux, B., S. Bernèche, and W. Im. 2000. Ion channels, permeation, and electrostatics: Insight into the function of KcsA. Biochemistry. 39:13295-13306.
Roux, B., and M. Karplus. 1993. Ion-Transport in the Gramicidin Channel - Free-Energy of the Solvated Right-Handed Dimer in a Model Membrane. Journal of the American Chemical Society. 115:3250-3262.
Roux, B., and R. MacKinnon. 1999. The cavity and pore helices the KcsA K+ channel: Electrostatic stabilization of monovalent cations. Science. 285:100-102.
Roux, B., M. Nina, R. Pomès, and J.C. Smith. 1996. Thermodynamic stability of water molecules in the bacteriorhodopsin proton channel: A molecular dynamics free energy perturbation study. Biophysical Journal. 71:670-681.
Roux, B., H.A. Yu, and M. Karplus. 1990. Molecular-Basis for the Born Model of Ion Solvation. Journal of Physical Chemistry. 94:4683-4688.
Woo, H.J., and B. Roux. 2005. Calculation of absolute protein-ligand binding free energy from computer simulations. Proc. Natl. Acad. Sci. U.S.A. 102:6825-6830.
Woolf, T.B., and B. Roux. 1994. Molecular-Dynamics Simulation of the Gramicidin Channel in a Phospholipid-Bilayer. Proc. Natl. Acad. Sci. U.S.A. 91:11631-11635.
Woolf, T.B., and B. Roux. 1997. The binding site of sodium in the gramicidin A channel: Comparison of molecular dynamics with solid-state NMR data. Biophysical Journal. 72:1930-1945.
Yu, H., S.Y. Noskov, and B. Roux. 2010. Two mechanisms of ion selectivity in protein binding sites. Proc. Natl. Acad. Sci. U.S.A. 107:20329-20334.
Zhou, Y., J.H. Morais-Cabral, A. Kaufman, and R. MacKinnon. 2001. Chemistry of ion coordination and hydration revealed by a K+ channel-Fab complex at 2.0 A resolution. Nature. 414:43-48.