Protein Design: in biro, in silico, in vitro and in vivo
Event details
| Date | 02.10.2017 |
| Hour | 12:15 |
| Speaker | Prof. Dek Woolfson, University of Bristol, Bristol (UK) |
| Location | |
| Category | Conferences - Seminars |
DISTINGUISHED LECTURE IN BIOLOGICAL ENGINEERING
(sandwiches served)
Abstract:
Protein design—that is, the construction of entirely new protein sequences that fold into prescribed structures—has come of age. It is now possible to design proteins de novo using simple rules of thumb or computational design methods. The designs can be made rapidly via peptide synthesis or the expression of synthetic genes; and the resulting proteins can usually be characterised all the way through to high-resolution X-ray crystal structures. Contemporary questions in the protein-design field include: What do with these new-found skills? What protein structures and functions do we target? How far can we move past the confines of natural protein structures and functions? And, how do we make protein design accessible to all, including non-specialists interested in tackling real-life biological and technological problems?
This talk will address these questions with reference to simple through to complex and functional protein designs that we have explored over the past 5 – 10 years. These use a straightforward protein structure, called the alpha-helical coiled coil, which are bundles of 2 or more alpha helices found in many protein-protein interactions. As such it provides an excellent basis for building proteins from the bottom up.
The vast majority of coiled-coil designs have been based on simple rules of thumb learnt from natural proteins or derived empirically through experiment.1 These rules relate sequence to structure to guide the specification of coiled-coil oligomerization state, strand orientation, partner selection, and, to some extent, stability. This has been extremely informative and productive, and design and engineering is probably more advanced for coiled coils than for any other protein structure.2 However, to move past the low-hanging fruit of coiled-coil design, and into the so-called dark matter of protein structures, we will all have to learn new tricks. To address this we have begun to tackle coiled-coil design parametrically using computational methods.3 We have developed easy-to-use computational modelling tools4 and a more-sophisticated suite of programs called ISAMBARD5 that allow the rapid generation and optimisation of protein designs in silico.
The talk will describe how a serendipitous discovery of a 6-stranded alpha-helical barrel6 led us to develop these computational methods; and how we have used them to deliver entirely new non-natural protein structures predictably.7 It will demonstrate the utility of this approach to make water-soluble protein-like barrels and pores, which we have engineered to form materials, bind small molecules, and catalyse simple reactions.8,9 Most recently with the Bayley lab (Oxford), we have engineered membrane-soluble variants of these alpha-helical barrels that insert into lipid bilayers and conduct ions in a voltage-dependent manner.10 The talk will touch on how the barrels and related structures are improving our general understanding of coiled coils.
1. The design of coiled-coil structures and assemblies.
DN Woolfson. Adv Prot Chem 70, 79-112 (2005)
2. Coiled-coil design: updated and upgraded.
DN Woolfson. Subcellular Biochemistry 82, 35-61 (2017)
3. De novo protein design: how do we expand into the universe of possible protein structures?
DN Woolfson et al. Curr Opin Struct Biol 33, 16-26 (2015)
4. CCBuilder: an interactive web-based tool for building, designing and assessing coiled-coil-protein assemblies.
CW Wood et al. Bioinformatics 30, 3029-3035 (2014)
5. ISAMBARD: an open-source computational environment for biomolecular analysis, modelling and design
CW Wood et al. Bioinformatics In press (2017)
6. A de novo peptide hexamer with a mutable channel.
NR Zaccai et al. Nature Chem Biol 7, 935-941 (2011)
7. Computational design of water-soluble a-helical barrels.
AR Thomson et al., Science 346, 485-488 (2014)
8. Modular design of self-assembling peptide-based nanotubes.
NC Burgess et al. J Am Chem Soc 137, 10554-10562 (2015)
9. Installing hydrolytic activity into a completely de novo protein framework.
AJ Burton et al., Nature Chem 8, 837-844 (2016)
10. A monodisperse a-helical peptide barrel.
KR Mahendran et al., Nature Chem 9, 411-419, (2017)
Bio:
Prof. Dek Woolfson took his first degree in Chemistry at the University of Oxford in 1987. He then did a PhD at the University of Cambridge followed by post-doctoral research at University College London and the University of California, Berkeley. After 10 years as Lecturer through to Professor of Biochemistry at the University of Sussex, he moved to the University of Bristol in 2005 to take up a joint chair in Chemistry and Biochemistry. His research has always been at the interface between chemistry and biology, applying chemical methods and principles to understand biological phenomena. Specifically, his group is interested in the challenge of rational protein design, how this can be applied in synthetic biology and biotechnology, and with a particular emphasis on making completely new protein structures and functions, and also biomaterials for applications in biotechnology, cell biology and medicine.
Prof. Woolfson is Director of BrisSynBio, a BBSRC/EPSRC-funded Synthetic Biology Research Centre.
Lunch with the speaker after the talk (for grad students and postdocs only): sign up here for one of nine slots (first come, first served...).
(sandwiches served)
Abstract:
Protein design—that is, the construction of entirely new protein sequences that fold into prescribed structures—has come of age. It is now possible to design proteins de novo using simple rules of thumb or computational design methods. The designs can be made rapidly via peptide synthesis or the expression of synthetic genes; and the resulting proteins can usually be characterised all the way through to high-resolution X-ray crystal structures. Contemporary questions in the protein-design field include: What do with these new-found skills? What protein structures and functions do we target? How far can we move past the confines of natural protein structures and functions? And, how do we make protein design accessible to all, including non-specialists interested in tackling real-life biological and technological problems?
This talk will address these questions with reference to simple through to complex and functional protein designs that we have explored over the past 5 – 10 years. These use a straightforward protein structure, called the alpha-helical coiled coil, which are bundles of 2 or more alpha helices found in many protein-protein interactions. As such it provides an excellent basis for building proteins from the bottom up.
The vast majority of coiled-coil designs have been based on simple rules of thumb learnt from natural proteins or derived empirically through experiment.1 These rules relate sequence to structure to guide the specification of coiled-coil oligomerization state, strand orientation, partner selection, and, to some extent, stability. This has been extremely informative and productive, and design and engineering is probably more advanced for coiled coils than for any other protein structure.2 However, to move past the low-hanging fruit of coiled-coil design, and into the so-called dark matter of protein structures, we will all have to learn new tricks. To address this we have begun to tackle coiled-coil design parametrically using computational methods.3 We have developed easy-to-use computational modelling tools4 and a more-sophisticated suite of programs called ISAMBARD5 that allow the rapid generation and optimisation of protein designs in silico.
The talk will describe how a serendipitous discovery of a 6-stranded alpha-helical barrel6 led us to develop these computational methods; and how we have used them to deliver entirely new non-natural protein structures predictably.7 It will demonstrate the utility of this approach to make water-soluble protein-like barrels and pores, which we have engineered to form materials, bind small molecules, and catalyse simple reactions.8,9 Most recently with the Bayley lab (Oxford), we have engineered membrane-soluble variants of these alpha-helical barrels that insert into lipid bilayers and conduct ions in a voltage-dependent manner.10 The talk will touch on how the barrels and related structures are improving our general understanding of coiled coils.
1. The design of coiled-coil structures and assemblies.
DN Woolfson. Adv Prot Chem 70, 79-112 (2005)
2. Coiled-coil design: updated and upgraded.
DN Woolfson. Subcellular Biochemistry 82, 35-61 (2017)
3. De novo protein design: how do we expand into the universe of possible protein structures?
DN Woolfson et al. Curr Opin Struct Biol 33, 16-26 (2015)
4. CCBuilder: an interactive web-based tool for building, designing and assessing coiled-coil-protein assemblies.
CW Wood et al. Bioinformatics 30, 3029-3035 (2014)
5. ISAMBARD: an open-source computational environment for biomolecular analysis, modelling and design
CW Wood et al. Bioinformatics In press (2017)
6. A de novo peptide hexamer with a mutable channel.
NR Zaccai et al. Nature Chem Biol 7, 935-941 (2011)
7. Computational design of water-soluble a-helical barrels.
AR Thomson et al., Science 346, 485-488 (2014)
8. Modular design of self-assembling peptide-based nanotubes.
NC Burgess et al. J Am Chem Soc 137, 10554-10562 (2015)
9. Installing hydrolytic activity into a completely de novo protein framework.
AJ Burton et al., Nature Chem 8, 837-844 (2016)
10. A monodisperse a-helical peptide barrel.
KR Mahendran et al., Nature Chem 9, 411-419, (2017)
Bio:
Prof. Dek Woolfson took his first degree in Chemistry at the University of Oxford in 1987. He then did a PhD at the University of Cambridge followed by post-doctoral research at University College London and the University of California, Berkeley. After 10 years as Lecturer through to Professor of Biochemistry at the University of Sussex, he moved to the University of Bristol in 2005 to take up a joint chair in Chemistry and Biochemistry. His research has always been at the interface between chemistry and biology, applying chemical methods and principles to understand biological phenomena. Specifically, his group is interested in the challenge of rational protein design, how this can be applied in synthetic biology and biotechnology, and with a particular emphasis on making completely new protein structures and functions, and also biomaterials for applications in biotechnology, cell biology and medicine.
Prof. Woolfson is Director of BrisSynBio, a BBSRC/EPSRC-funded Synthetic Biology Research Centre.
Lunch with the speaker after the talk (for grad students and postdocs only): sign up here for one of nine slots (first come, first served...).
Practical information
- Informed public
- Free
Organizer
Contact
- Institute of Bioengineering (IBI, Christina Mattsson)