Theory and Simulation of Biomolecules within the Energy Landscapes Framework
Lead Research Organisation:
University of Cambridge
Department Name: Chemistry
Abstract
This project will involve theory and simulation of biomolecules within the energy landscapes framework. In particular, we will investigate the possibilities for control and design of multifunctional biomaterials with the capability to switch between conformations. The landscapes will be explored using the Cambridge energy landscape exploration codes GMIN, OPTIM and PATHSAMPLE, exploiting the new CUDA interface for GPU hardware with the AMBER potential.
Possible test systems include xylo-nucleic acid (XyloNA) and polyproline helices. The first system, XyloNA, is a synthetic analogue of ribo-nucleic acid (RNA), where the ribose sugar has been replaced by xylose. Previous simulations reveal the uncoiling or elongation of an initial conformation to form an open ladder type transient state conformation and the subsequent formation of a highly flexible duplex with a tendency to coil in a left-handed fashion. Polyproline peptides may offer another potential for design of biomolecular switches, since they can form both left- (PPII) and right-handed (PPI) helices. The all-cis polyproline I (PPI) helix is favoured in aliphatic alcohols, whereas the all-trans polyproline II (PPII) helix is favoured in aqueous solutions. Ion mobility experiments have recently examined the intermediate steps associated with the process of Polyproline-13 (Pro13) conversion from the PPI helix to the PPII helix upon solvent exchange. The results suggest the presence of two major conformers, identified as the PPI and PPII helices. Further analysis indicates a transition mechanism with sequential cis-trans isomerisations followed by a parallel process to establish PPII and two smaller subpopulations at equilibrium. It appears that prolines sequentially flip from cis to trans starting from the N-terminus. The corresponding energy landscape is therefore expected to exhibit a hierarchical structure of subfunnels, which might be exploited to switch between alternative structures.
Possible test systems include xylo-nucleic acid (XyloNA) and polyproline helices. The first system, XyloNA, is a synthetic analogue of ribo-nucleic acid (RNA), where the ribose sugar has been replaced by xylose. Previous simulations reveal the uncoiling or elongation of an initial conformation to form an open ladder type transient state conformation and the subsequent formation of a highly flexible duplex with a tendency to coil in a left-handed fashion. Polyproline peptides may offer another potential for design of biomolecular switches, since they can form both left- (PPII) and right-handed (PPI) helices. The all-cis polyproline I (PPI) helix is favoured in aliphatic alcohols, whereas the all-trans polyproline II (PPII) helix is favoured in aqueous solutions. Ion mobility experiments have recently examined the intermediate steps associated with the process of Polyproline-13 (Pro13) conversion from the PPI helix to the PPII helix upon solvent exchange. The results suggest the presence of two major conformers, identified as the PPI and PPII helices. Further analysis indicates a transition mechanism with sequential cis-trans isomerisations followed by a parallel process to establish PPII and two smaller subpopulations at equilibrium. It appears that prolines sequentially flip from cis to trans starting from the N-terminus. The corresponding energy landscape is therefore expected to exhibit a hierarchical structure of subfunnels, which might be exploited to switch between alternative structures.
People |
ORCID iD |
| David John Wales (Primary Supervisor) | |
| Daniel Sharpe (Student) |
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| EP/N509620/1 | 01/10/2016 | 30/09/2022 | |||
| 1944641 | Studentship | EP/N509620/1 | 01/10/2017 | 31/03/2021 | Daniel Sharpe |
| Description | I have developed various numerical methods to perform quantitative analysis of a class of models ("transition networks") that appear as models for the stochastic dynamics of various systems in many disciplines. For instance, transition networks can be used to model the spread of a disease in a population, the distribution of species in an ecosystem, financial markets, and more. The methods I have developed are specialised to deal with models having mathematical properties that greatly complicate their analysis by computation, namely that the models feature a "rare event". For instance, elimination of a disease in a population is a rare event compared to small fractions of the population becoming infected and recovering, which takes place frequently and on short timescales. In applications of these analysis methods in my own work, I have primarily focused on biophysical problems such as modeling the folding transitions of peptides and nucleic acids. |
| Exploitation Route | Various code is publically available online, mostly at github.com/danieljsharpe. The framework that I have developed is highly general, and deals with a class of models that appear not only in condensed matter physics and biophysics but also in systems biology, epidemiology, ecology, economic and social studies, and more. |
| Sectors | Financial Services, and Management Consultancy,Pharmaceuticals and Medical Biotechnology |
| Description | Energy landscapes for tRNA halves |
| Organisation | Pasteur Institute of Montevideo |
| Country | Uruguay |
| Sector | Charity/Non Profit |
| PI Contribution | Contributed to sampling and analysis of databases of stationary points for the potential energy landscapes of so-called "tRNA halves" |
| Collaborator Contribution | Sampling and analysis of databases of stationary points for the potential energy landscapes of so-called "tRNA halves" |
| Impact | A paper detailed the mechanisms for conformational rearrangements in so-called "tRNA halves" is forthcoming. |
| Start Year | 2018 |
| Description | Kinetic transition networks for DNA duplex hybridisation |
| Organisation | University of Science and Technology of China USTC |
| Country | China |
| Sector | Academic/University |
| PI Contribution | Contributed to sampling databases of stationary points on the potential energy landscapes for hybridisation of DNA duplexes, development and application of methods to analyse the resulting transition networks. |
| Collaborator Contribution | Sampling databases of stationary points on the potential energy landscapes for hybridisation of DNA duplexes, application of analysis methods |
| Impact | Published simulation results for the hybridisation of DNA hexamer duplexes (https://pubs.acs.org/doi/abs/10.1021/acs.jpclett.9b02356). To date, this is the longest sequence for which DNA hybridisation has been modeled at the all-atom level. The results yield fundamental insight into the mechanistic features of the hybridisation process, with practical implications for drug design. A second paper, dealing with the mechanisms of DNA hybridisation for longer sequences modelled at a more coarse-grained level, is forthcoming. |
| Start Year | 2018 |
| Description | Stochastic path integrals and kinetic transition networks |
| Organisation | University of Massachusetts |
| Country | United States |
| Sector | Academic/University |
| PI Contribution | Development and application of numerical methods to solve the linear master equation for arbitrary transition networks. |
| Collaborator Contribution | Mathematical development of new theories for solving the linear master equation for arbitrary transition networks, and development and application of algorithms and numerical methods for based on the new theory. |
| Impact | This project is ongoing. Code has been developed, and is publically available online eg at github.com/danieljsharpe, and a description of the new theories and methods are currently being written. |
| Start Year | 2019 |
| Description | Waiting time distributions in kinetic transition networks |
| Organisation | Aix-Marseille University |
| Country | France |
| Sector | Academic/University |
| PI Contribution | Design and application of accelerated simulation methods and development of other numerical methodologies for the analysis of Markovian transition networks. |
| Collaborator Contribution | Design and application of advanced numerical methods for the analysis of Markovian transition networks. |
| Impact | Some code to perform numerical analysis of Markovian transition networks is publically available online, eg at github.com/danieljsharpe. At least one publication is forthcoming. |
| Start Year | 2019 |
| Title | DISCOTRESS |
| Description | DISCOTRESS (DIscrete State COntinuous Time Rare Event Simulation Suite) is a general program for the simulation and analysis of the stochastic dynamics on arbitrary linear transition networks. |
| IP Reference | |
| Protection | Copyrighted (e.g. software) |
| Year Protection Granted | 2020 |
| Licensed | Yes |
| Impact | DISCOTRESS contains implementations of various algorithms for the simulation and analysis of the stochastic dynamics on arbitrary linear transition networks within a highly flexible framework. Some of these algorithms are new or previously-described implementations were not publically available. Linear transition network models appear in condensed matter physics, biophysics, systems biology, epidemiology, ecology, economic and social studies, and other disciplines. |
| Title | DISCOTRESS |
| Description | DISCOTRESS (DIscrete State COntinuous Time Rare Event Simulation Suite) is a general program for the simulation and analysis of the stochastic dynamics on arbitrary linear transition networks. |
| Type Of Technology | Software |
| Year Produced | 2020 |
| Open Source License? | Yes |
| Impact | DISCOTRESS contains implementations of various algorithms for the simulation and analysis of the stochastic dynamics on arbitrary linear transition networks within a highly flexible framework. Some of these algorithms are new or previously-described implementations were not publically available. Linear transition network models appear in condensed matter physics, biophysics, systems biology, epidemiology, ecology, economic and social studies, and other disciplines. |
| URL | http://github.com/danieljsharpe |