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Multi-resolution simulations of intracellular processes

Event

Location

Kavli Royal Society Centre, Chicheley Hall, Newport Pagnell, Buckinghamshire, MK16 9JJ

Overview

Theo Murphy international scientific meeting organised by Professor Radek Erban, Dr Sarah Harris and Dr Raffaello Potestio.

Intracellular processes, copyright: Dr Raffaello Potestio

Multi-resolution methods for spatio-temporal modelling of intracellular processes have potential to bridge the gap between all-atom molecular dynamics simulations and stochastic reaction-diffusion models in the macroscopic limit. This scientific meeting will bring together mathematicians, biophysicists and computational biologists to discuss the development of new multi-resolution methods, the analysis of their accuracy, convergence and efficiency, and biological applications.

The schedule of talks and speaker biographies are available below. Recorded audio of the presentations will be available on this page after the meeting has taken place.

Poster session

There will be a poster session at 17:00 on Monday 24 September. If you would like to apply to present a poster please submit your proposed title, abstract (not more than 200 words and in third person), author list, name of the proposed presenter and institution to the Scientific Programmes team no later than Friday 7 September 2018. Please note that places are limited and posters are selected at the scientific organiser's discretion. Poster abstracts will only be considered if the presenter is registered to attend the meeting.

Attending the event

This is a residential conference, which allows for increased discussion and networking

  • Free to attend
  • Advanced registration essential (please request an invitation)
  • Catering and accommodation available to purchase during registration

Enquiries: contact the Scientific Programmes team

Event organisers

Select an organiser for more information

Schedule of talks

24 September

09:00-12:30

Session 1

5 talks Show detail Hide detail

Chairs

Professor Radek Erban, University of Oxford, UK

09:00-09:05 Welcome by the Royal Society and organisers

09:05-09:30 Polymer/lipids membranes

Dr Paola Carbone, University of Manchester, UK

Abstract

Block copolymers are largely used in pharmacological formulation and may represent a breakthrough in the development of controlled drug/gene release systems or cell activities regulators. The identification of the key molecular interactions responsible for the destabilization of the cell membrane represents the first milestone towards a rational design of these biomaterials. Modelling can guide the understanding of the effect that biological active copolymers have on the structure and stability of lipid membranes. This talk will focus on a specific family of amphiphilic block copolymer known as Pluronic and will clarify the mechanism of membrane adhesion and breakage and their effect on the phase diagram of the lipid bilayers. The simulations reveal that the incorporation of the polymer chains leads to membranes that can sustain increasing mechanical stresses. Analysis of mechanical, structural, and dynamic properties of the membrane shows that the polymer chains interact strongly with the lipids in the vicinity, restraining their mobility and imparting better mechanical stability to the membrane. The hybrid membranes under tension remain thicker, more ordered, and stiffer in comparison to their lipid analogues. Trans-bilayer lipid movements (flip-flop) are observed and appear to be triggered by the presence of the polymer chains. A careful analysis of the pore formation under high tensions reveals two distinctive mechanisms that depend on the distribution of the hydrophilic polymer blocks in the bilayer. Finally, Dr Carbone will show that the incorporation of the polymers modifies the nature of the liquid/gel phase transition of the membrane.

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09:30-09:45 Discussion

09:45-10:15 Addressing the dynamics of Flaviviruses with multiscale simulations

Sergio Pantano, Institute Pasteur, Montevideo, Uruguay

Abstract

Multi-resolution simulations combine the best of two worlds by keeping detailed information on specific regions of interest while capturing the essence of less relevant parts of molecular systems. A simultaneous fine-grain (FG)/coarse-grain (CG)/supra-coarse grain (SG) simulation scheme, which maintains accuracy in the FG region at statistical precision, will be introduced in this talk. This framework can be used in combination with popular atomistic force fields or with the SIRAH force field for CG/SG simulations. Applications of this hybrid solvation method to comparative simulations of Zika, Dengue and Japanese Encephalitis viruses will be discussed.

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10:15-10:30 Discussion

10:30-11:00 Coffee

11:00-11:30 Towards simulating a minimal cell: integration of experiment and theory

Professor Zan Luthey-Schulten, University of Illinois, USA

Abstract

Ribosomes - the primary macromolecular machines responsible for translating the genome into proteins - are complexes of precisely folded RNA and proteins. The ways in which their production and assembly are managed by the living cell is of deep biological importance. Our whole-cell model of ribosome biogenesis in a slowing growing bacteria includes the effects of growth, DNA replication, translation, ribosome assembly, and cell division. All biological processes are described in terms of reaction-diffusion master equations (RDME) and solved stochastically using the GPU-based Lattice Microbes simulation software over a cell cycle. The replication parameters are derived from single cell measurements of gene copy numbers in a series of E. coli strains with fluorescently labeled genes as a function of cell length and time. The work on biogenesis can now be linked with the essential metabolism of a minimal bacterial cell, JCVI-Syn3A.  To treat processes at biologically relevant length- (microns), time- (hours), and concentration- (nanomolar to millimolar) scales requires hybrid RDME simulations. Professor Luthey-Schulten will report on our efforts to develop a complete kinetic model of a minimal bacterial cell.

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11:30-11:45 Discussion

11:45-12:15 Langevin dynamics, parameterization, and Cucker-Smale flocking

Professor Ben Leimkuhler, University of Edinburgh, UK

Abstract

Langevin dynamics is a family of stochastic models that facilitate computational study of complex systems in the presence of unresolved subscale interactions; as such, it is a key tool for biological simulation from nano to macro scales. In this talk Professor Leimkuhler will describe the recent work on the mathematical underpinnings of Langevin dynamics, ranging from foundations to parameterisation to numerical analysis. As an example, Professor Leimkuhler will describe a simple stochastic model relevant for flocking/streaming in biological systems.

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12:15-12:30 Discussion

12:30-13:30

Lunch

13:30-17:00

Session 2

4 talks Show detail Hide detail

Chairs

Professor Raffaello Potestio, University of Trento, Italy

13:30-14:00 Unravelling the activation of neuroreceptors at the molecular level

Professor Carla Molteni, King's College London, UK

Abstract

Pentameric ligand-gated ion channels (pLGICs), embedded in the membrane of nerve cells, important neuroreceptors that mediate fast synaptic transmission, are involved in several neurological disorders and are target sites for drugs and, in invertebrates, insecticides. However, there is little idea of how they function at the molecular level due to their complexity, limited experimental information and the challenges they pose to simulations. The group has investigated the first crucial step of their activation mechanism, which consists in the binding of a neurotransmitter to their extracellular domain, focusing of the prototypical case of the neurotransmitter GABA binding to the insect RDL receptor, which is linked to the resistance to the insecticide dieldrin.

Using the "funnel-metadynamics" computational technique, which efficiently enhances the sampling of bound and unbound states using a funnel-shaped restraining potential to limit the exploration in the solvent, Professor Molteni describes the binding free energy landscape, identified the chain of events leading the neurotransmitter from the solvent into the binding-pocket and estimated the binding affinity. Moreover, the talk will show how this landscape is disrupted by mutations which prevent the receptor to function. The group also assessed the potential of a trans-cis proline switch for the gating of the ion channel, in the case of the 5-HT3 receptor, which is activated by serotonin. The RDL and the 5-HT3 receptors share structural and functional features with other pLGICs, hence this work provides valuable protocols to study the activation mechanisms of pLGICs at the molecular level beyond conventional docking and molecular dynamics techniques.

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14:00-14:15 Discussion

14:15-14:45 Multi-scale simulations of neuronal G-protein coupled receptors

Professor Paolo Carloni, Forschungszentrum Jülich, Germany

Abstract

Human G-protein coupled receptors (GPCRs) constitute a large membrane receptor superfamily. About half of those (~420) recognize taste and odorant molecules. These “chemical senses” GPCRs are involved in a variety of physiological processes and they constitute promising targets for pharmaceutical intervention. Here, Professor Carloni will present recent multi-resolution (coarse-grain/molecular mechanics) simulations studies, which lead to predictions of agonists’ binding to the receptors, consistently with molecular biology experiments. The talk will conclude that multi resolution approaches as that present here may assist structural predictions of membrane proteins, like chemical senses GPCRs, for which experimental structural information is lacking.

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14:45-15:00 Discussion

15:00-15:30 Tea

15:30-16:00 Coupling molecular dynamics simulations with Brownian dynamics

Professor Radek Erban, University of Oxford, UK

Abstract

Professor Erban will discuss mathematical and computational methods for spatio-temporal modelling in molecular and cell biology, including all-atom and coarse-grained molecular dynamics (MD), Brownian dynamics (BD), stochastic reaction-diffusion models and macroscopic mean-field equations. Microscopic (BD, MD) models are based on the simulation of trajectories of individual molecules and their localized interactions (for example, reactions). Mesoscopic (lattice-based) stochastic reaction-diffusion approaches divide the computational domain into a finite number of compartments and simulate the time evolution of the numbers of molecules in each compartment, while macroscopic models are often written in terms of mean-field reaction-diffusion partial differential equations for spatially varying concentrations.

The discussion will cover the development, analysis and applications of multi-resolution methods for spatio-temporal modelling of intracellular processes, which use (detailed) BD or MD simulations in localized regions of particular interest (in which accuracy and microscopic details are important) and a (less-detailed) coarser model in other regions in which accuracy may be traded for simulation efficiency. Professor Erban will discuss error analysis and convergence properties of the developed multi-resolution methods, their software implementation and applications of these multiscale methodologies to modelling of intracellular calcium dynamics, actin dynamics and DNA dynamics. Professor Erban will also discuss the development of multiscale methods which couple MD and coarser stochastic models in the same dynamic simulation.

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16:00-16:15 Discussion

16:15-17:00 Toward a refined electrostatic description for biomolecules simulations: introducing an effective pH and titration scheme to a coarse-grained nucleic acids model

Professor Samuela Pasquali, University Paris Descartes, France

Abstract

Electrostatic interactions play a pivotal role in many (bio)molecular association processes. The molecular organization and function in biological systems are largely determined by these interactions from pure Coulombic contributions to more peculiar mesoscopic forces due to ion-ion correlation and proton fluctuations. By means of constant-pH Monte Carlo simulations based on a fast coarse-grained titration proton scheme, a new computer molecular model was devised to study protein-RNA interactions and compute local pka values for RNA molecules.

Our results illustrate the importance of the charge regulation mechanism that enhances the association between biological macromolecules in a similar way as observed for other protein-polyelectrolyte systems typically found in colloidal science. Due to the highly negative charge of RNA, the effect is more pronounced in this system as predicted by the Kirkwood-Shumaker theory. These efficient calculations have now been coupled to coarse-grained simulations of nucleic acids to include the role of conformational changes. Professor Pasquali will present this work in progress to obtain pH-dependent coarse-grained nucleic acids simulations.

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16:45-17:00 Discussion

25 September

09:00-12:30

Session 3

4 talks Show detail Hide detail

Chairs

Dr Sarah Harris, University of Leeds, UK

09:00-09:30 Data driven Bayesian selection for coarse-grained models of liquid water

Dr Julija Zavadlav, ETH Zurich, Switzerland

Abstract

Coarse-graining (CG) is essential for molecular modeling to access time and length scales that are computationally beyond the reach of the conventional atomistic simulations. Despite numerous advances, coarse-graining often involves making several a priori assumptions, which are rarely systematically addressed.  Dr Zavadlav investigates a number of CG models that differ in the level of coarse-graining and in the model complexity. The group will deploy Classical and Hierarchical Bayesian to quantify and calibrate the uncertainty of the models and to perform the model selection using experimental data.

In this work it is found that compared to the single interaction site models the multiple sites models can be used at higher levels of coarse-graining. These models behave similarly in terms of reproducing the experimental data, however, they significantly differ in the computational cost. The group observed no significant improvement of models when going from rigid to flexible models, thus implying that one should use rigid geometries for efficiency reasons. Dr Zavadlav will present a data-informed rationale for the selection of CG water models and provide guidance for future water model designs.

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09:30-09:45 Discussion

09:45-10:15 Uniform vs. position-dependent coarse-graining: challenges and opportunities from variable resolution biomolecular modelling

Professor Raffaello Potestio, University of Trento, Italy

Abstract

All-atom models of soft matter systems promise realism and accuracy, at the price of intense computational effort and difficult parametrisation. Coarse-grained models offer faster sampling of larger systems for lighter computational effort, at the price of lower accuracy and -alas- difficult parametrisation. A deceptively simple way to take advantage of high- and low-resolution models is to make one in between - not so coarse, yet not too accurate; Such models are highly specialised, and might easily result in an unsatisfactory compromise. Alternatively, one can try to make a model that is both coarse and accurate, distributing the detail unevenly across the system. Multiple-resolution approaches combine in the same model two or more different representations, keeping the resolution high where chemical accuracy is necessary and employing a coarser description where possible. These methods have been developed for and applied to gases, liquids, solids, polymers, proteins, crystals and other systems. They are effective in reducing the computational cost of a simulation and useful to gain understanding of the system and its physico-chemical properties. Yet, the construction of multiple-resolution models is not free from conceptual and practical difficulties, and several open questions are in place when dealing with them.

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10:15-10:30 Discussion

10:30-11:00 Coffee Break

11:00-11:30 Optimising cancer treatment by combining small-molecule cytotoxic drugs and nanoparticles: An in-silico quantitative analysis

Dr Vasileios Vavourakis, University College London, UK

Abstract

The role of the tumour/host microenvironment mechano-biology and the mechanisms involved in the delivery of anti-cancer drugs is heavily investigated using in-vitro or/and in-vivo models. However, in-silico models offer a promising alternative to contemplate tumour progression, and the major factors affecting the transport of tumour-targeting molecules. Thus, Dr Vavourakis will present here a three-dimensional, cancer-specific, in-silico modelling framework of solid-tumour growth, angiogenesis and drug delivery. The model is novel in that it describes in a coupled and multiscale manner the drug transport in the vascular network and the tumour interstitial space, the interaction of the chemotherapeutic agent with the extracellular matrix, tumour regression as a function of the drug concentration, the remodelling of the tumour vasculature in response to the drug, and the biomechanics of the tumour and the host tissue.

To identify optimal delivery of a cancer-killing drug, the group carried out a parametric analysis of in-silico cancer development / drug delivery simulations with respect to the binding properties of the chemotherapeutic agent and the tumour blood vessels permeability. The simulations describe a single-dose bolus injection of either small-sized molecules (1 nm) or a drug-borne nanoparticle (150 nm). The in-silico results suggest that tumour response to treatment is strongly dependent on the drug binding properties rather than the permeability of the tumour vessels. Importantly, increasing the binding affinity of the drug, remodels the tumour vasculature to obtain a more normal structure, thus, improving its functionality. These findings also suggest that enhancing the binding rate, the range of bolus injection time-window during which the tumour vasculature can be normalized become wider; which can lead to higher levels of perfused tumour vessels that may allow the delivery of higher drug concentrations to the tumour interstitial space in follow-up injections.

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11:30-11:45 Discussion

11:45-12:15 Towards Simulating Eukaryotic Cells at Single Molecule Resolution

Professor Garegin Papoian, University of Maryland, USA

Abstract

One of the key unsolved challenges at the interface of physical and life sciences is to formulate comprehensive computational modeling of the whole eukaryotic cell, at a single molecule resolution, which would deeply integrate reaction-diffusion, mechanical-structural and transport processes of cell's salient mechanochemical modules. Towards addressing this problem, the group has developed a unique reactive mechanochemical force-field and software, called MEDYAN (Mechanochemical Dynamics of Active Networks: http://medyan.org). MEDYAN integrates dynamics of multiple mutually interacting phases: 1) a spatially resolved solution phase is treated using a reaction-diffusion master equation; 2) a polymeric gel phase is both chemically reactive and also undergoes complex mechanical deformations; 3) flexible membrane boundaries interact mechanically and chemically with both solution and gel phases. The above-mentioned computational components constitute the fundamental ingredients for minimal modeling of eukaryotic cells at a single molecule resolution. In this talk, Professor Papoian will outline our recent progress in simulating multi-micron scale cytosolic/cytoskeletal dynamics at 1000 seconds timescale, and also highlight the outstanding challenges in bringing about the capability for routine molecular modeling of eukaryotic cells.

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12:15-12:30 Discussion

12:30-13:30

Lunch

13:30-17:00

Session 4

4 talks Show detail Hide detail

Chairs

Professor Radek Erban, University of Oxford, UK

13:30-14:00 Dimensionality reduction aides scale-bridging in multi-resolution simulations of conformational landscapes

Professor Christine Peter, University of Konstanz, Germany

Abstract

Simulations have become an important complement to experimental structural biological approaches since they provide a molecular-level view on structural ensembles and dynamics of conformational transitions or aggregation processes on ns to ms timescales. In recent years, multiscale simulation methods that combine classical atomistic and coarse grained levels of resolution have gained popularity in the biomolecular simulation community. While the coarse grained level extends the accessible length and timescales compared to an all-atom model, a systematic link to an atomistic level of resolution allows to maintain information from a more accurate representation.

In the talk, Professor Peter will present an example of how such a multiresolution approach in combination with advanced analysis methods can be used to investigate and characterize the structural variability of multidomain proteins and protein conjugates. Professor Peter will show how dimensionality reduction can be employed to characterize the sampling of free energy landscapes of such multidomain systems and to assess the consistency of the sampling in models at different levels of resolution. These methods are optimally suited to identify, compare, and classify relevant conformational states and to guide the interpretation of the simulations with respect to experimental data.

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14:00-14:15 Discussion

14:15-14:45 Multiscale modelling of complex biomolecular systems

Dr Dmitry Nerukh, Aston University, UK

Abstract

Recent experimental and computational advances allow investigations of liquid biomolecular solutions at spatial and temporal scales (nanometers, nanoseconds) where two representations are equally valid and necessary: atomistic and continuous (fluid dynamics). Examples of the former include MD simulations of systems composed of tens of millions of atoms or cryo-EM measurements of complete viruses and cell organelles with atomistic resolution. The latter is represented, for example, by the multitude of nano- and micro-fluidic devices including, among others, non-contact liquid atomic force microscopy capable of measuring flows of liquids at atomistic scales. Despite comparable quality of theoretical predictions using both atomistic and continuum representations, the physics behind them is fundamentally different, from the basic concepts (discrete atoms vs continuum of matter) to the equations of motion describing the system’s structure and dynamics. This disparity becomes particularly obvious if the problem at hand requires transition between the scales or the description of the same system at different scales simultaneously.

Dr Nerukh will present the recent attempts to develop a unified description of liquid systems such that they are described by the same equations of motion throughout multiple scales, from atomistic to macroscopic hydrodynamic. Two different frameworks will be described each having a set of equations that are valid equations of motion at both limiting scales, MD and hydrodynamic, and at all scales between these extremes. The frameworks are physically consistent, obeying fundamental conservation laws (of mass, momentum, and energy) at all scales. Examples of applying these frameworks to the complete virus in aqueous solution and flows in nanofluidic channel will also be given.

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14:45-15:00 Discussion

15:00-15:30 Tea break

15:00-15:30 Tea

15:30-16:00 No equations, no variables, no parameters, no space, no time: data and the modelling of complex systems

Professor Yannis G Kevrekidis, Johns Hopkins University, USA

Abstract

Obtaining predictive dynamical equations from data lies at the heart of science and engineering modeling, and is the linchpin of our technology. In mathematical modeling one typically progresses from observations of the world (and some serious thinking!) first to equations for a model, and then to the analysis of the model to make predictions. Good mathematical models give good predictions (and inaccurate ones do not) - but the computational tools for analyzing them are the same: algorithms that are typically based on closed form equations.

While the skeleton of the process remains the same, today we witness the development of mathematical techniques that operate directly on observations -data-, and appear to circumvent the serious thinking that goes into selecting variables and parameters and deriving accurate equations. The process then may appear to the user a little like making predictions by "looking in a crystal ball". Yet the "serious thinking" is still there and uses the same -and some new- mathematics: it goes into building algorithms that jump directly from data to the analysis of the model (which is now not available in closed form) so as to make predictions. This work here presents a couple of efforts that illustrate this "new” path from data to predictions. It really is the same old path, but it is travelled by new means.

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16:00-16:15 Discussion

16:15-17:00 Overview, future directions and discussion

Dr Sarah Harris, University of Leeds, UK

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