Electron Delocalization in Polypeptide Structure and Stability
Lead Research Organisation:
University of Bristol
Department Name: Chemistry
Abstract
Context: Biology is a molecular science: it is blueprinted by, built from and run by molecules. Not surprisingly, therefore, interdisciplinary research between the biological and physical sciences is critical. We are interested in the interface of biology and chemistry, and the field of chemical biology, which seeks to explore, explain, and exploit biological phenomena using chemical principles and methods. In this proposal, we aim to develop an understanding of a new class of weak bonds, so-called "n-to-pi* interactions", believed to contribute to stabilizing protein molecules in their correctly defined and functional 3-D shapes.
"Biomolecules" come in all shapes and sizes. The larger ones are called biological macromolecules, and include: carbohydrates, lipids, nucleic acids (e.g., DNA) and proteins. Most perform tasks in biology dictated by their chemistry. Proteins are unusual in that they have many different functions. For example, collagen provides the scaffolding in body tissues; haemoglobin transports oxygen from the lungs to organs; and hexokinase is an enzyme--a protein that speeds up chemical reactions-that helps break down glucose--containing foodstuffs to make ATP, the universal currency of energy in biology.
The functions of most proteins depend on them adopting specific 3-D shapes. Proteins are polymers, or chain-like molecules made from similar building blocks called amino acids, which are held together by strong "covalent" bonds. However, the reason that proteins form 3-D structures is due to a different type of bonding, known as "weak", or "non-covalent interactions". Possibly the best-known weak interactions are "hydrogen bonds". These are responsible for water being a liquid (rather than a gas) at ambient temperatures on most of the Earth's surface; as such, hydrogen bonds are probably the most important bonds for life on the planet.
Because hydrogen bonds and similar interactions are weak, they are hard to detect, probe and study. Importantly, because these interactions are weak they are easily made and broken, which allows biological structures to be dynamic. This transience is essential in biology, but, again, makes studying non-covalent interactions difficult. Many weak interactions are required to conspire, or cooperate to provide enough energy to fold and stabilize whole protein structures. For example, the average protein structure is held in place by hundreds of hydrogen bonds.
Aims, objectives and potential benefits: Over the past two years we have worked with Prof Ron Raines's team at the University of Madison-Wisconsin, USA to explore another type of weak interaction that we thought might be important in proteins. In many respects, these n-to-pi* interactions are cousins of hydrogen bonds. To our surprise, when we inspected the structures of natural proteins we found many examples of n-to-pi* interactions; indeed, in some proteins they were as prolific as hydrogen bonds. This discovery changes our picture of protein structure and stability. It also has implications for experimental and theoretical scientists aiming for a better understanding of proteins, both for its own sake, and to allow more-predictable engineering of proteins leading to potential applications in biotechnology and medicine.
We propose to continue our work with Prof Raines. We will be responsible for doing computational studies, so-called bioinformatics, to look for more examples of n-to-pi* interactions and to examine them in detail; and we hope to find examples of other weak interactions that people may have missed. Our work will guide Prof Raines' experimental group, who will aim to engineer better and stronger n-to-pi* interactions into model proteins. Finally, we plan to coalesce this information in improved computer methods of n-to-pi* interactions to benefit academic and industrial researchers who are interested in modeling proteins to aid fundamental and applied protein science and chemical biology.
"Biomolecules" come in all shapes and sizes. The larger ones are called biological macromolecules, and include: carbohydrates, lipids, nucleic acids (e.g., DNA) and proteins. Most perform tasks in biology dictated by their chemistry. Proteins are unusual in that they have many different functions. For example, collagen provides the scaffolding in body tissues; haemoglobin transports oxygen from the lungs to organs; and hexokinase is an enzyme--a protein that speeds up chemical reactions-that helps break down glucose--containing foodstuffs to make ATP, the universal currency of energy in biology.
The functions of most proteins depend on them adopting specific 3-D shapes. Proteins are polymers, or chain-like molecules made from similar building blocks called amino acids, which are held together by strong "covalent" bonds. However, the reason that proteins form 3-D structures is due to a different type of bonding, known as "weak", or "non-covalent interactions". Possibly the best-known weak interactions are "hydrogen bonds". These are responsible for water being a liquid (rather than a gas) at ambient temperatures on most of the Earth's surface; as such, hydrogen bonds are probably the most important bonds for life on the planet.
Because hydrogen bonds and similar interactions are weak, they are hard to detect, probe and study. Importantly, because these interactions are weak they are easily made and broken, which allows biological structures to be dynamic. This transience is essential in biology, but, again, makes studying non-covalent interactions difficult. Many weak interactions are required to conspire, or cooperate to provide enough energy to fold and stabilize whole protein structures. For example, the average protein structure is held in place by hundreds of hydrogen bonds.
Aims, objectives and potential benefits: Over the past two years we have worked with Prof Ron Raines's team at the University of Madison-Wisconsin, USA to explore another type of weak interaction that we thought might be important in proteins. In many respects, these n-to-pi* interactions are cousins of hydrogen bonds. To our surprise, when we inspected the structures of natural proteins we found many examples of n-to-pi* interactions; indeed, in some proteins they were as prolific as hydrogen bonds. This discovery changes our picture of protein structure and stability. It also has implications for experimental and theoretical scientists aiming for a better understanding of proteins, both for its own sake, and to allow more-predictable engineering of proteins leading to potential applications in biotechnology and medicine.
We propose to continue our work with Prof Raines. We will be responsible for doing computational studies, so-called bioinformatics, to look for more examples of n-to-pi* interactions and to examine them in detail; and we hope to find examples of other weak interactions that people may have missed. Our work will guide Prof Raines' experimental group, who will aim to engineer better and stronger n-to-pi* interactions into model proteins. Finally, we plan to coalesce this information in improved computer methods of n-to-pi* interactions to benefit academic and industrial researchers who are interested in modeling proteins to aid fundamental and applied protein science and chemical biology.
Planned Impact
Who will benefit from the research?
We anticipate that the following groups will benefit, and in this approximate order, from the proposed research that we plan to conduct:
1. General researchers in the areas of peptide and protein science and chemical biology.
2. Computational scientists working in all aspects of protein modeling.
3. The researcher employed on the grant in the UK, Dr Gail Bartlett (GJB).
4. Post-doctoral researchers and post-graduate students in the collaborating laboratory of Prof Raines.
5. The wider UK and international academic communities, particularly those involved in bioinformatics, and chemical and structural biology.
6. The University of Bristol and collaborating universities.
7. Public and private education.
8. UK Public.
9. UK & US industry and technology bases.
10. UK & US Economies.
How will they benefit from the research?
We envisage that they will benefit in the following ways, and over the approximate time frames given in brackets
1. Our discovery of widespread n-to-pi* interactions in proteins is fundamental science, which underpins the intellectual and theoretical base of protein science and chemical biology. (potentially 1 - many years)
2. Our work aims to provide a better understanding of weak non-covalent forces in proteins. As such it will impact on force fields and computational methods that aim to capture and apply these. (potentially 1 - many years)
3 & 4. GJB and researchers in the collaborating research groups will receive training and experience, and gain new skills in interdisciplinary research, benefiting their personal development and enhancing their career prospects. (1 - 5+ years)
5-7. This research and training will supply the public and private education and research bases with highly skilled researchers, educators and trainers experienced in interdisciplinary research and teaching. (5 - 10 years)
8. In the immediate term, DNW and GJB will also engage the public and school pupils, at events such as Science Cafes, Public Engagement Forums and school visits. (1 - 5 years) Both currently engage in and lead such events. We have already posted a general article about our findings thus far as a University of Bristol press release: http://www.bristol.ac.uk/news/2010/7126.html
9 & 10. Some of the trained researchers may end up supporting the UK and US industrial and technology bases by taking up jobs in these sectors, specifically in the biotechnology and pharmaceutical industries. In this way, there are potential long-term benefits to the UK economy. (5 - 25 years)
We anticipate that the following groups will benefit, and in this approximate order, from the proposed research that we plan to conduct:
1. General researchers in the areas of peptide and protein science and chemical biology.
2. Computational scientists working in all aspects of protein modeling.
3. The researcher employed on the grant in the UK, Dr Gail Bartlett (GJB).
4. Post-doctoral researchers and post-graduate students in the collaborating laboratory of Prof Raines.
5. The wider UK and international academic communities, particularly those involved in bioinformatics, and chemical and structural biology.
6. The University of Bristol and collaborating universities.
7. Public and private education.
8. UK Public.
9. UK & US industry and technology bases.
10. UK & US Economies.
How will they benefit from the research?
We envisage that they will benefit in the following ways, and over the approximate time frames given in brackets
1. Our discovery of widespread n-to-pi* interactions in proteins is fundamental science, which underpins the intellectual and theoretical base of protein science and chemical biology. (potentially 1 - many years)
2. Our work aims to provide a better understanding of weak non-covalent forces in proteins. As such it will impact on force fields and computational methods that aim to capture and apply these. (potentially 1 - many years)
3 & 4. GJB and researchers in the collaborating research groups will receive training and experience, and gain new skills in interdisciplinary research, benefiting their personal development and enhancing their career prospects. (1 - 5+ years)
5-7. This research and training will supply the public and private education and research bases with highly skilled researchers, educators and trainers experienced in interdisciplinary research and teaching. (5 - 10 years)
8. In the immediate term, DNW and GJB will also engage the public and school pupils, at events such as Science Cafes, Public Engagement Forums and school visits. (1 - 5 years) Both currently engage in and lead such events. We have already posted a general article about our findings thus far as a University of Bristol press release: http://www.bristol.ac.uk/news/2010/7126.html
9 & 10. Some of the trained researchers may end up supporting the UK and US industrial and technology bases by taking up jobs in these sectors, specifically in the biotechnology and pharmaceutical industries. In this way, there are potential long-term benefits to the UK economy. (5 - 25 years)
Organisations
People |
ORCID iD |
Dek Woolfson (Principal Investigator) |
Publications
Wood CW
(2014)
CCBuilder: an interactive web-based tool for building, designing and assessing coiled-coil protein assemblies.
in Bioinformatics (Oxford, England)
Woolfson DN
(2012)
New currency for old rope: from coiled-coil assemblies to a-helical barrels.
in Current opinion in structural biology
Steinkruger JD
(2012)
The d'--d--d' vertical triad is less discriminating than the a'--a--a' vertical triad in the antiparallel coiled-coil dimer motif.
in Journal of the American Chemical Society
Hudson KL
(2015)
Carbohydrate-Aromatic Interactions in Proteins.
in Journal of the American Chemical Society
Bartlett GJ
(2013)
Interplay of hydrogen bonds and n?p* interactions in proteins.
in Journal of the American Chemical Society
Steinkruger JD
(2012)
Strong contributions from vertical triads to helix-partner preferences in parallel coiled coils.
in Journal of the American Chemical Society
Boyle AL
(2012)
Squaring the circle in peptide assembly: from fibers to discrete nanostructures by de novo design.
in Journal of the American Chemical Society
Baker E
(2015)
Local and macroscopic electrostatic interactions in single a-helices
in Nature Chemical Biology
Bartlett GJ
(2016)
On the satisfaction of backbone-carbonyl lone pairs of electrons in protein structures.
in Protein science : a publication of the Protein Society
Newberry RW
(2014)
Signatures of n?p* interactions in proteins.
in Protein science : a publication of the Protein Society
Description | Better understanding of non-covalent interactions in proteins - ie the fundamentals of what holds protein molecules together and makes them work. |
Exploitation Route | Building new computer algorithms for protein structure prediction and design. |
Sectors | Education Manufacturing including Industrial Biotechology Pharmaceuticals and Medical Biotechnology |
Title | CCBuilder |
Description | A computational method and GUI for design and engineering of coiled-coil assemblies of all oligomer states. |
Type Of Technology | Software |
Year Produced | 2014 |
Open Source License? | Yes |
Impact | Being used and adopted by national and international research groups. |
URL | http://coiledcoils.chm.bris.ac.uk/app/cc_builder/ |
Description | Parliamentary Science Committee presentation 2014 |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Policymakers/politicians |
Results and Impact | Approximately 200 people attended the Parliamentary and Scientific Committee meeting on the 17th June 2014. The audience included Parliamentarians, members of scientific bodies, science-based industry and academics. http://www.scienceinparliament.org.uk/sample-page/programme/ This meeting has subsequently been written up and included in the Autumn 2014 Science in Parliament (Vol 71 No 4: pgs 20 - 26) publication. Unknown |
Year(s) Of Engagement Activity | 2014 |
URL | http://www.scienceinparliament.org.uk/wp-content/uploads/2013/09/Autumn-Contents-page.pdf |
Description | The rise and rise of synthetic biology in the UK: science, policy and public perception |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Policymakers/politicians |
Results and Impact | Invited to Houses of Parliament, London, UK, June 2014, to speak to the Parliamentary and Scientific Committee. |
Year(s) Of Engagement Activity | 2014 |
URL | http://www.scienceinparliament.org.uk/wp-content/uploads/2014/05/17-June-AGM-agenda.pdf |