Co-evolution Analysis for Allosteric Network
Lead Research Organisation:
University of Oxford
Department Name: SABS CDT
Abstract
Allosteric regulation is a common mechanism in the protein world but little is known about the underlying mechanisms on a residue level. Allosteric regulators modulate a protein's or a protein complex's functionality by binding at a site which is distant to the active catalytic site. How this allosteric signal is transmitted from a distant allosteric site to the proteins' active site is an open research question.
This project links the analysis of allostery with the analysis of co-evolution of protein residues. Co-evolution occurs when the interaction between two (or potentially more) residues is crucial for a protein's stability or functionality. If one of the interacting residues mutates, the other is likely to mutate as well. These residue-residue couplings can be derived from multiple sequence alignments where column-wise correlations are extracted and interactions (contacts) are thus inferred.
Previous work has shown that there is information about allostery in contact prediction networks derived from statistical coupling analysis (SCA). The main paper on this studied only one system (MutS) and used several arbitrary parameters. Therefore, this research was set up to build an improved allosteric network prediction pipeline.
First, by using more recent co-evolution analysis methods that have higher precision in contact predictions such as CCMpred or metaPSICOV, which are based on direct coupling analysis (DCA) instead of statistical coupling analysis. The main difference between these two underlying methodologies is the direct coupling analyses' capability to discriminate between true evolutionary correlations and transitive correlations, a common problem in correlation analysis. Second, using solely sequence information to remove the crystal structure dependence of the previous approach which would allow allostery predictions on a much larger scale and third, automation of the allosteric network prediction and selection of important residues for signal transmission by computing network centrality measures.
There are not many tools available to analyse allostery, especially no high-throughput ones, so developing and improving such basic tools could be a first step of in the process of understanding allosteric signal transmission. Furthermore, the prediction on a residue-specific level might enable the control of allosteric functions for the investigation on allosteric drugs acting in a non-competitive way. This, for example, could be beneficial for combination therapies where pathologically relevant proteins are targeted not only by one drug but two drugs acting at different sites which could be improving therapeutical effectiveness and avoiding drug resistance.
This project falls within the EPSRC Biological Informatics research area and is supported by F. Hoffmann-La Roche and UCB, two companies of the healthcare sector that can provide valuable expertise in research questions but also in translating findings into improvements of drug discovery efforts.
This project links the analysis of allostery with the analysis of co-evolution of protein residues. Co-evolution occurs when the interaction between two (or potentially more) residues is crucial for a protein's stability or functionality. If one of the interacting residues mutates, the other is likely to mutate as well. These residue-residue couplings can be derived from multiple sequence alignments where column-wise correlations are extracted and interactions (contacts) are thus inferred.
Previous work has shown that there is information about allostery in contact prediction networks derived from statistical coupling analysis (SCA). The main paper on this studied only one system (MutS) and used several arbitrary parameters. Therefore, this research was set up to build an improved allosteric network prediction pipeline.
First, by using more recent co-evolution analysis methods that have higher precision in contact predictions such as CCMpred or metaPSICOV, which are based on direct coupling analysis (DCA) instead of statistical coupling analysis. The main difference between these two underlying methodologies is the direct coupling analyses' capability to discriminate between true evolutionary correlations and transitive correlations, a common problem in correlation analysis. Second, using solely sequence information to remove the crystal structure dependence of the previous approach which would allow allostery predictions on a much larger scale and third, automation of the allosteric network prediction and selection of important residues for signal transmission by computing network centrality measures.
There are not many tools available to analyse allostery, especially no high-throughput ones, so developing and improving such basic tools could be a first step of in the process of understanding allosteric signal transmission. Furthermore, the prediction on a residue-specific level might enable the control of allosteric functions for the investigation on allosteric drugs acting in a non-competitive way. This, for example, could be beneficial for combination therapies where pathologically relevant proteins are targeted not only by one drug but two drugs acting at different sites which could be improving therapeutical effectiveness and avoiding drug resistance.
This project falls within the EPSRC Biological Informatics research area and is supported by F. Hoffmann-La Roche and UCB, two companies of the healthcare sector that can provide valuable expertise in research questions but also in translating findings into improvements of drug discovery efforts.
Planned Impact
The main impact of the SABS CDT will be the difference made by the scientists trained within it, both during their DPhils and throughout their future careers.
The impact of the students during their DPhil should be measured by the culture change that the centre engenders in graduate training, in working at the interface between mathematical/physical sciences and the biomedical sciences, and in cross sector industry/academia working practices.
Current SABS projects are already changing the mechanisms of industry academic collaboration, for example as described by one of our Industrial Partners
"UCB and Roche are currently supervising a joint DPhil project and have put in two more joint proposals, which would have not been possible without the connections and the operational freedom offered by SABS-IDC and its open innovation culture, a one-of-the-kind in UK's CDTs."
New collaborations are also being generated: over 25% of current research projects are entirely new partnerships brokered by the Centre. The renewal of SABS will allow it to continue to strengthen and broaden this effect, building new bridges and starting new collaborations, and changing the culture of academic industrial partnerships. It will also continue to ensure that all of its research is made publically available through its Open Innovation structure, and help to create other centres with similar aims.
For all of our partners however, the students themselves are considered to be the ultimate output: as one our partners describes it,
"I believe the current SABS-IDC has met our original goals of developing young research scientists in a multidisciplinary environment with direct industrial experience and application. As a result, the graduating students have training and research experience that is directly applicable to the needs of modern lifescience R&D, in areas such as pharmaceuticals and biotechnology."
However, it is not only within the industrial realm that students have impact; in the later years of their DPhils, over 40% of SABS students, facilitated by the Centre, have undertaken various forms of public engagement. This includes visiting schools, working alongside Zooniverse to develop citizen science projects, and to produce educational resources in the area of crystal images. In the new Centre all students will be required to undertake outreach activities in order to increase engagement with the public.
The impact of the students after they have finished should be measured by how they carry on this novel approach to research, be it in the sector or outside it. As our industrial letters of support make clear, though no SABS students have yet completed their DPhils, there is a clear expectation that they will play a significant role in shaping the UK economy in the future. For example, as one of our partners comments about our students
"UCB has been in constant search for such talents, who would thrive in pharmaceutical research, but they are rare to find in conventional postgraduate programmes. Personally I am interested in recruiting SABS-IDC students to my group once they are ready for the job market."
To demonstrate the type of impact that SABS alumni will have, we consider the impact being made by the alumni of the i-DTC programmes from which this proposal has grown. Examples include two start-up companies, both of which already have investment in the millions. Several students also now hold senior positions in industry and in research facilities and institutes. They have also been named on 30 granted or pending patents, 15 of these arising directly from their DPhil work.
The examples of past success given above indicate the types of impact we expect the graduates from SABS to achieve, and offer clear evidence that SABS students will become future research leaders, driving innovation and changing research culture.
The impact of the students during their DPhil should be measured by the culture change that the centre engenders in graduate training, in working at the interface between mathematical/physical sciences and the biomedical sciences, and in cross sector industry/academia working practices.
Current SABS projects are already changing the mechanisms of industry academic collaboration, for example as described by one of our Industrial Partners
"UCB and Roche are currently supervising a joint DPhil project and have put in two more joint proposals, which would have not been possible without the connections and the operational freedom offered by SABS-IDC and its open innovation culture, a one-of-the-kind in UK's CDTs."
New collaborations are also being generated: over 25% of current research projects are entirely new partnerships brokered by the Centre. The renewal of SABS will allow it to continue to strengthen and broaden this effect, building new bridges and starting new collaborations, and changing the culture of academic industrial partnerships. It will also continue to ensure that all of its research is made publically available through its Open Innovation structure, and help to create other centres with similar aims.
For all of our partners however, the students themselves are considered to be the ultimate output: as one our partners describes it,
"I believe the current SABS-IDC has met our original goals of developing young research scientists in a multidisciplinary environment with direct industrial experience and application. As a result, the graduating students have training and research experience that is directly applicable to the needs of modern lifescience R&D, in areas such as pharmaceuticals and biotechnology."
However, it is not only within the industrial realm that students have impact; in the later years of their DPhils, over 40% of SABS students, facilitated by the Centre, have undertaken various forms of public engagement. This includes visiting schools, working alongside Zooniverse to develop citizen science projects, and to produce educational resources in the area of crystal images. In the new Centre all students will be required to undertake outreach activities in order to increase engagement with the public.
The impact of the students after they have finished should be measured by how they carry on this novel approach to research, be it in the sector or outside it. As our industrial letters of support make clear, though no SABS students have yet completed their DPhils, there is a clear expectation that they will play a significant role in shaping the UK economy in the future. For example, as one of our partners comments about our students
"UCB has been in constant search for such talents, who would thrive in pharmaceutical research, but they are rare to find in conventional postgraduate programmes. Personally I am interested in recruiting SABS-IDC students to my group once they are ready for the job market."
To demonstrate the type of impact that SABS alumni will have, we consider the impact being made by the alumni of the i-DTC programmes from which this proposal has grown. Examples include two start-up companies, both of which already have investment in the millions. Several students also now hold senior positions in industry and in research facilities and institutes. They have also been named on 30 granted or pending patents, 15 of these arising directly from their DPhil work.
The examples of past success given above indicate the types of impact we expect the graduates from SABS to achieve, and offer clear evidence that SABS students will become future research leaders, driving innovation and changing research culture.
