Intrinsically Multifunctional Energy Landscapes: A New Paradigm for Molecular Design

Lead Research Organisation: University of Cambridge
Department Name: Chemistry

Abstract

This project aims to advance theory and computer simulation to understand and design molecules capable of functioning as nanoscale devices. The inspiration comes from a recent study of an "intrinsically disordered" protein, which suggests new design principles for systems that can be switched in a controlled fashion between alternative configurations.

The underlying theoretical framework is based on analysis of the potential energy landscape, which defines the variation of potential energy with particle positions for any molecular or condensed matter system. In particular, we formulate observable properties in terms of local minima on the energy landscape, and the transition states and pathways that connect them. Within a well-defined set of approximations, this view reduces the corresponding computational framework largely to geometry optimisation. The results are translated into experimental observables using the tools of statistical mechanics and unimolecular rate theory. The applications will address two Priority Areas: nanoscale design of functional materials, and understanding of biological processes.

In previous work, we have established that systems with self-organising properties are associated with funnelled potential energy landscapes, where configurations are guided downhill towards a target morphology. This paradigm establishes a universality class, which includes magic number clusters (such as buckminsterfullerene), crystallisation, self-assembly, and protein folding. The realisation that intrinsically disordered proteins define an alternative class of behaviour leads us to consider a new paradigm for multifunctional systems. The research hypothesis addressed in the present proposal is that multifunctional molecules are associated with multifunnel energy landscapes. Understanding how naturally occurring systems exploit this capability, for example to bind different ligands, will provide design principles for artificial nanodevices that are switchable between alternative structures.

Project goals will be achieved through a series of work packages:

(1) Recent advances in methodology will be exploited to access experimental time and length scales. Implementing the corresponding computer programs on graphics processing units can provide efficiency gains exceeding two orders of magnitude. A variety of new ideas to further transform the sampling will be implemented and tested.

(2) Intrinsically disordered proteins can perform multiple cellular functions by binding different partners. We aim to test the hypothesis that multiple functions are associated with an intrinsically multifunnel potential energy landscape. The focussing effect of binding partners on the structure of the landscape will be examined for two particular proteins.

(3) The evolution of specificity for antibodies in the presence of antigens will be analysed in terms of the underlying landscape. Structure prediction and the effect of antigen binding and successive mutation will be related to changes in dynamics.

(4) Multifunnel landscapes will be investigated for nucleic acids. Competition between G-quadruplex structures is predicted to result in alternative morphologies separated by high barriers, which may represent important targets for drug discovery. Design principles for ultraresponsive DNA-based devices will be deduced for structures that incorporate fast-folding segments.

(5) The insight gained in the above projects will be used to design artificial nanodevices. Here we will consider switching via both external conditions, such as applied fields, and internal degrees of freedom that are accessible experimentally. For example, devices based upon helix inversion have the potential to couple linear and rotatory motion. To exploit this possibility we will design a photoswitchable chiral ligand. Transitions between the B and Z forms of DNA can also provide a route to nanoscale switches.

Planned Impact

This project focuses on new theory and computer simulation techniques to understand the appearance of multifunctional behaviour and specificity in natural systems, and the exploitation of this insight to design artificial nanodevices. The framework involved is rather general, and applications could therefore be exploited directly wherever molecular simulation is used. Hence the immediate (non-academic) impact of this research would include two distinct communities. First we have industrial research teams specifically concerned with construction of nanodevices or exploitation of multifunctional systems. The next-generation antibody therapeutics of interest to Janssen R&D falls into this category. In addition, new methodology is potentially useful for any industrial research that employs computer simulation to predict structure, dynamics, or thermodynamic properties of matter. Examples of specific consultancy arrangements and current discussions with industry illustrate the diversity of applications, which range from:

* computer simulation of antibody binding - this is the new project with Johnson and Johnson. The company has funded an internship to fund a PhD student from the group for a six month collaborative research visit to Philadelphia. This connection provides direct evidence of the importance of the proposed project for industry, and will facilitate rapid knowledge transfer and impact.
* prediction of binding affinities for potential drugs with biomolecules, particularly proteins, which requires us to treat both the structure and thermodynamics (previous project with Evotec OAI - new discussions with companies such as Eli Lilly and Astex)
* structure prediction for metal clusters deposited on surfaces (consultancy with Exxon)
* simulation of phase behaviour for gas hydrates relevant to the petrochemical industry (projects with InfoChem)

An important impact is to provide advantages in terms of research capacity. Transforming the accuracy and speed of predictions from computer simulation has the potential to provide a competitive edge for UK industry, with corresponding benefits for the economy. New opportunities for molecular computer simulation would attract additional investment in R&D programs, with corresponding benefits for the economy. Long term impacts could derive from the discovery of new drugs, providing the possibility of societal benefits within sectors concerned with human health. As a specific example, insight into loop structure and dynamics will have important applications in antibody therapeutic development. More accurate predictions for the properties of materials could help to inform policy making, for example, in terms of how alternative energy reserves based on gas hydrate deposits might usefully be exploited.

Much of this impact for non-academic beneficiaries depends on knowledge transfer, either to industry, or to policy makers. For specific applications in industry, knowledge transfer is greatly facilitated by exchange of students, and explicit consultancy agreements, as for the projects with Evotec, Exxon, and Johnson and Johnson. The latest Knowledge Transfer Fellowship just starting with Biovia, provides further evidence of the relevance and potential impact of this research. Here the focus is on mechanisms for catalysis.

Some particularly successful projects have been initiated by former group members following career paths in industry, who are aware of the enhanced simulation capabilities provided by the computational side of the potential energy landscapes framework. However, other projects, such as the Exxon collaboration, have resulted from dissemination of new methodology via lectures presented at larger international meetings, backed up by publications and information on the group web site. These activities will therefore be extended selectively, choosing invitations to meetings with a view to the potential opportunities that may result.

Publications

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Ballard A (2017) Energy landscapes for machine learning in Physical Chemistry Chemical Physics

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Calvo F (2016) Grand and Semigrand Canonical Basin-Hopping. in Journal of chemical theory and computation

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Carr JM (2016) Energy landscapes and persistent minima. in The Journal of chemical physics

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Chakraborty D (2016) Conformational Energy Landscape of the Ritonavir Molecule. in The journal of physical chemistry. B

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Cragnolini T (2017) Multifunctional energy landscape for a DNA G-quadruplex: An evolved molecular switch. in The Journal of chemical physics

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Eckhoff M (2017) Structure and Thermodynamics of Metal Clusters on Atomically Smooth Substrates. in The journal of physical chemistry letters

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Fackovec B (2016) Dynamical properties of two- and three-dimensional colloidal clusters of six particles. in Physical chemistry chemical physics : PCCP

 
Description We have tested the hypothesis that multifunctional systems in nature, including some proteins and nucleic acid, encode these different functions through multifunnel energy landscapes. The hypothesis has been validated for intrinsically disordered proteins and quadruplex structures in DNA. Signatures of multifunctional landscapes can now be diagnosed through a variety of new theoretical and computational tools, including detailed breakdown of heat capacity functions.

Common features have been identified for structural glasses, leading to a deeper understanding of the complex phenomenology of the glass transition.
Exploitation Route New methodology for structure prediction, enhanced thermodynamic sampling, and rare event dynamics is all available in public domain computer programs. Predictions for multifunctional materials, including switches that respond to external fields, temperature or pH, may be realised in future experiments.
Sectors Chemicals,Digital/Communication/Information Technologies (including Software),Healthcare,Pharmaceuticals and Medical Biotechnology

URL http://www-wales.ch.cam.ac.uk/CCD.html
 
Description Quantum International Frontiers, Honorary Committee member
Geographic Reach Asia 
Policy Influence Type Membership of a guideline committee
 
Description Royal Society Artificial Intelligence in Health and Care Panel
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
Impact Machine learning predictions for patient diagnostic support.
 
Description Royal Society FLAIR Fellowship panel
Geographic Reach Africa 
Policy Influence Type Membership of a guideline committee
 
Description Royal Society International Collaboration Awards Panel
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
 
Description Royal Society Research Grants Panel
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
 
Title GMIN 
Description computer program for global optimisation and enhanced thermodynamic sampling. 
Type Of Material Improvements to research infrastructure 
Provided To Others? Yes  
Impact worldwide use of group software. This is a key research tool, under constant development, including new approaches for multifunnel landscapes. 
URL http://www-wales.ch.cam.ac.uk/GMIN/
 
Title OPTIM 
Description Program for characterising pathways and mechanisms 
Type Of Material Improvements to research infrastructure 
Provided To Others? Yes  
Impact wordwide use of group software, This is a key research tool, under constant development. 
URL http://www-wales.ch.cam.ac.uk/OPTIM/
 
Title PATHSAMPLE 
Description Program for rare event dynamics and construction of kinetic transition networks 
Type Of Material Improvements to research infrastructure 
Year Produced 2010 
Provided To Others? Yes  
Impact Acceleration of rare event dynamics simulations in many groups, This is a development computer programme, which is constantly updated. The most recent changes are to treat multifunnel landscapes. 
URL http://www-wales.ch.cam.ac.uk/PATHSAMPLE/
 
Title Data set for "Decoupled Associative and Dissociative Processes in Strong yet Highly Dynamic Host-Guest Complexes" 
Description Data supporting the publication "Decoupled Associative and Dissociative Processes in Strong yet Highly Dynamic Host-Guest Complexes" 
Type Of Material Database/Collection of data 
Year Produced 2018 
Provided To Others? Yes  
 
Title Research Data supporting "Pathways for diffusion in the potential energy landscape of the network glass former SiO2", J. Chem. Phys. 147 (2017) 
Description Archive files containing the input files and (where relevant) source code to reproduce data on the dynamics and energy landscape of supercooled silica. The main components of the repository are as follows: source code and input files for producing MD trajectories for binary Lennard-Jones and BKS silica systems as used in the code, python scripts for analysing these trajectories, source code for identifying cage-breaking transitions in quenched trajectories, input files for the Cambridge Energy Landscape Software used to generate the landscape databases, and scripts for analysing those databases. 
Type Of Material Database/Collection of data 
Year Produced 2017 
Provided To Others? Yes  
 
Description Clusters of particles with short-range interactions 
Organisation Massey University
Country New Zealand 
Sector Academic/University 
PI Contribution Development of theory and associated computer programs to explore the energy landscapes of particles interacting via short-range forces, e.g. colloids.
Collaborator Contribution Computer simulation and theory to understand the structure and properties of colloidal clusters.
Impact From sticky-hard-sphere to Lennard-Jones-type clusters. L Trombach, RS Hoy, DJ Wales, P Schwerdtfeger - Physical review. E (2018) 97, 043309 (DOI: 10.1103/physreve.97.043309)
Start Year 2018
 
Description Crystals of electrons 
Organisation Pennsylvania State System of Higher Education
PI Contribution Prediction of the structure for electron bilayers in terms of classical charge distributions
Collaborator Contribution Prediction and analysis of quantum double-well structures for electron bilayers and hence electron bilayer crystals in a magnetic field
Impact Exotic bilayer crystals in a strong magnetic field WN Faugno, AJ Duthie, DJ Wales, JK Jain - Physical Review B (2018) 97, 245424 (DOI: 10.1103/physrevb.97.245424)
Start Year 2018
 
Description Insight into human disease from simulations of nucleic acids 
Organisation Florida Atlantic University
Country United States 
Sector Academic/University 
PI Contribution Development of computer programs for simulation of rare event dynamics,
Collaborator Contribution Simulations of nucleaic acids, e.g. RNA A-Bulges Related to Microtubule-Associated Protein Tau Causing Frontotemporal Dementia and Parkinsonism.
Impact Computational Investigation of RNA A-Bulges Related to Microtubule-Associated Protein Tau Causing Frontotemporal Dementia and Parkinsonism. DJ Wales, MD Disney, I Yildirim - Journal of Physical Chemistry B (2018) 123, 57 (DOI: 10.1021/acs.jpcb.8b09139) Improving Computational Predictions of Single-Stranded RNA Tetramers with Revised alpha/gamma Torsional Parameters for the Amber Force Field DJ Wales, I Yildirim - The Journal of Physical Chemistry B (2017) 121, 2989 (DOI: 10.1021/acs.jpcb.7b00819)
Start Year 2017
 
Description Structure and properties of DNA 
Organisation University of Gdansk
Country Poland 
Sector Academic/University 
PI Contribution Ongoing development of computer programs for exploration of energy landscapes.
Collaborator Contribution Structure and property predictions for DNA and RNA. Development of the NARES-2P force field.
Impact Computational Studies of the Mechanical Stability for Single-Strand Break DNA. P Krupa, DJ Wales, AK Sieradzan - J Phys Chem B (2018) 122, 8166 (DOI: 10.1021/acs.jpcb.8b05417) What Makes Telomeres Unique? AK Sieradzan, P Krupa, DJ Wales - Journal of Physical Chemistry B (2017) 121, 2207 (DOI: 10.1021/acs.jpcb.6b08780)
Start Year 2017
 
Description Theory support for experimental work on microfluidic droplets 
Organisation University of Cambridge
Department Cambridge University Health Partners
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Energy landscape interpretation of experimental results for aggregation of a-Synuclein
Collaborator Contribution Experimental investigation of protein misfolding and amyloid formation using microfluidics
Impact Mapping Surface Hydrophobicity of a-Synuclein Oligomers at the Nanoscale J-E Lee, JC Sang, M Rodrigues, AR Carr, MH Horrocks, S De, MN Bongiovanni, P Flagmeier, CM Dobson, DJ Wales, SF Lee, D Klenerman - Nano Lett (2018) 18, 7494 (DOI: 10.1021/acs.nanolett.8b02916)
Start Year 2018
 
Description Tunnelling and intermolecular forces 
Organisation University of California, Berkeley
Department School of Public Health Berkeley
Country United States 
Sector Academic/University 
PI Contribution Theory and simulations to predict and explain experimental results of quantum tunnelling.
Collaborator Contribution State-of-the-art high resolution spectroscopy: far-infrared vibration-rotation tunnelling spectroscopy using cavity ring-down methods.
Impact Terahertz VRT Spectroscopy of the Water Hexamer-h12 Cage: Dramatic Libration-Induced Enhancement of Hydrogen Bond Tunneling Dynamics WTS Cole, Ö Yönder, AA Sheikh, RS Fellers, MR Viant, RJ Saykally, JD Farrell, DJ Wales - The journal of physical chemistry. A (2018) 122, 7421 (DOI: 10.1021/acs.jpca.8b05777) Terahertz VRT spectroscopy of the water hexamer-d(12) prism: Dramatic enhancement of bifurcation tunneling upon librational excitation WTS Cole, JD Farrell, AA Sheikh, Ö Yönder, RS Fellers, MR Viant, DJ Wales, RJ Saykally - The Journal of Chemical Physics (2018) 148, 094301 (DOI: 10.1063/1.5006195)
 
Description machine learning landscapes 
Organisation United Technologies Research Center (UTRC)
Country United States 
Sector Public 
PI Contribution Development of theory and computer programs for exploring the loss function landscapes of neural networks.
Collaborator Contribution Calculations for specific systems to investigate the predictive power of neural networks. Analysis of kinetic transition networks to explore small world and scale-free properties.
Impact Loss surface of XOR artificial neural networks D Mehta, X Zhao, EA Bernal, DJ Wales - Phys Rev E (2018) 97, 052307 (DOI: 10.1103/PhysRevE.97.052307) Properties of kinetic transition networks for atomic clusters and glassy solids. JWR Morgan, D Mehta, DJ Wales - Physical Chemistry Chemical Physics (2017) 19, 25498 (DOI: 10.1039/C7CP03346J) Energy landscapes for machine learning. AJ Ballard, R Das, S Martiniani, D Mehta, L Sagun, JD Stevenson, DJ Wales - Physical chemistry chemical physics : PCCP (2017) 19, 12585 (DOI: 10.1039/c7cp01108c)
Start Year 2017
 
Description  
IP Reference  
Protection Protection not required
Year Protection Granted
Licensed Yes
Impact The OPTIM program has been licenced for use by Biovia. The licence defines a subset of functionality. Ongoing development of the program has been used in the public domain version, which is employed by groups worldwide.
 
Title GMIN 
Description global optimisation 
Type Of Technology Software 
Year Produced 2016 
Open Source License? Yes  
Impact widespread use of basin-hopping 
URL http://www-wales.ch.cam.ac.uk/GMIN/
 
Title GROMACS/GMIN interface 
Description The interface puts GMIN global optimisation algorithms in communication with energy and gradient computations by GROMACS. 
Type Of Technology Software 
Year Produced 2018 
Open Source License? Yes  
Impact This software opens to a broad spectrum of applications of basin-hopping minimisation, exploiting the versatility of GROMACS. 
 
Title GROMACS/OPTIM interface 
Description The interface puts in communication OPTIM geometric optimisation algorithms and reaction pathways calculations with energy and gradient computations by GROMACS. 
Type Of Technology Software 
Year Produced 2019 
Open Source License? Yes  
Impact This software opens to a broad spectrum of applications of pathways calculation, through eigenvector-following algorithms, exploiting the versatility of GROMACS. 
 
Title OPTIM 
Description characterisation of pathways and mechanisms 
Type Of Technology Software 
Year Produced 2016 
Open Source License? Yes  
Impact widespread use of hybrid eigenvector-following 
URL http://www-wales.ch.cam.ac.uk/OPTIM/
 
Title PATHSAMPLE 
Description Harvesting a kinetic transition network for analysis of rare event dynamics. Calculation of phenomenological rates. 
Type Of Technology Software 
Year Produced 2016 
Open Source License? Yes  
Impact Widespread use of discrete path sampling 
URL http://www-wales.ch.cam.ac.uk/PATHSAMPLE/