ABSTRACT
The combination of molecular simulation and low-resolution experimental data as a route to peptide and protein structure: applications to bioactive peptides and antibody-antigen complexes
Structural knowledge at the atomic level is essential for a complete understanding of biological function. Current approaches to determine molecular structure typically involve high-resolution methods, including X-ray crystallography, nuclear magnetic resonance spectroscopy (NMR), and, increasingly, cryoEM. However, these methods have their limitations, for example, being in the solid state, at low temperature, or requiring isotopic labelling. Small angle X-ray scattering (SAXS), on the other hand, provides structural information in the solution phase at room temperature, but is limited in terms of resolution. In this presentation, I will describe computer simulation approaches to extend the structural information available from low resolution techniques. In the first part of my presentation, enhanced sampling molecular dynamics simulations will be combined with calculations of NMR chemical shifts to explore the conformational equilibria of a range of bioactive peptides, thereby elucidating the most probable solution-phase structures of these intrinsically disordered peptides, and relating these structures to biological function. In the second part, normal and enhanced-sampling molecular dynamics will be combined with experimental SAXS data, to determine the conformations of isolated antibody F(ab) domains in solution, and also the solution-phase binding geometries of antibody-antigen complexes. Through this combination of techniques, a detailed structural interpretation of the agonistic and antagonistic behaviour of a closely related series of antibodies to CD32B will be discussed.
BIO
Jonathan W. Essex is Professor of Computational Chemistry at the University of Southampton. He is Deputy Head of the School of Chemistry, and Co-Director of the EPSRC Centre for Doctoral Training in Theory and Modelling in Chemical Sciences. He obtained his DPhil as a Glaxo Research Scholar from the University of Oxford under the supervision of Graham Richards, before taking up a NATO Postdoctoral Fellowship with Bill Jorgensen at Yale University. He then returned to the UK as a Royal Society University Research Fellow at the University of Southampton. His research interests lie in the development and application of computer simulation methodology as applied to biological systems, with a particular interest in free energy calculations, coarse-grain and hybrid simulations, and enhanced sampling methods. He was awarded the Marlow Medal by the Royal Society of Chemistry in 2002 and a Royal Society Wolfson Research Merit Award in 2013.
The combination of molecular simulation and low-resolution experimental data as a route to peptide and protein structure: applications to bioactive peptides and antibody-antigen complexes
Structural knowledge at the atomic level is essential for a complete understanding of biological function. Current approaches to determine molecular structure typically involve high-resolution methods, including X-ray crystallography, nuclear magnetic resonance spectroscopy (NMR), and, increasingly, cryoEM. However, these methods have their limitations, for example, being in the solid state, at low temperature, or requiring isotopic labelling. Small angle X-ray scattering (SAXS), on the other hand, provides structural information in the solution phase at room temperature, but is limited in terms of resolution. In this presentation, I will describe computer simulation approaches to extend the structural information available from low resolution techniques. In the first part of my presentation, enhanced sampling molecular dynamics simulations will be combined with calculations of NMR chemical shifts to explore the conformational equilibria of a range of bioactive peptides, thereby elucidating the most probable solution-phase structures of these intrinsically disordered peptides, and relating these structures to biological function. In the second part, normal and enhanced-sampling molecular dynamics will be combined with experimental SAXS data, to determine the conformations of isolated antibody F(ab) domains in solution, and also the solution-phase binding geometries of antibody-antigen complexes. Through this combination of techniques, a detailed structural interpretation of the agonistic and antagonistic behaviour of a closely related series of antibodies to CD32B will be discussed.
BIO
Jonathan W. Essex is Professor of Computational Chemistry at the University of Southampton. He is Deputy Head of the School of Chemistry, and Co-Director of the EPSRC Centre for Doctoral Training in Theory and Modelling in Chemical Sciences. He obtained his DPhil as a Glaxo Research Scholar from the University of Oxford under the supervision of Graham Richards, before taking up a NATO Postdoctoral Fellowship with Bill Jorgensen at Yale University. He then returned to the UK as a Royal Society University Research Fellow at the University of Southampton. His research interests lie in the development and application of computer simulation methodology as applied to biological systems, with a particular interest in free energy calculations, coarse-grain and hybrid simulations, and enhanced sampling methods. He was awarded the Marlow Medal by the Royal Society of Chemistry in 2002 and a Royal Society Wolfson Research Merit Award in 2013.