In pursuit of an accurate spatial and temporal model of biomolecules at the atomistic level: a perspective on computer simulation

Gray, Alan; Harlen, Oliver G.; Harris, Sarah A.; Khalid, Syma; Leung, Yuk Ming; Lonsdale, Richard; Mulholland, Adrian J.; Pearson, Arwen R.; Read, Daniel J.; Richardson, Robin A.

doi:10.1107/s1399004714026777

Cited by 11 publications

(14 citation statements)

References 52 publications

(46 reference statements)

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“…Traditionally MD simulations of MPs have been performed at the atomistic (AT) level of resolution, where each atom is explicitly considered (with the exception of 'united atom' models in which nonpolar hydrogen atoms are considered implicitly) 44 . These simulations have been successful for elucidating details of e.g.…”

Section: Opportunity For Use In Molecular Simulationmentioning

confidence: 99%

Encapsulated membrane proteins: A simplified system for molecular simulation

Lee¹,

Khalid²,

Pollock³

et al. 2016

Biochimica et Biophysica Acta (BBA) - Biomembranes

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A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT 2Over the past 50 years there has been considerable progress in our understanding of biomolecular interactions at an atomic level. This in turn has allowed molecular simulation methods employing full atomistic modeling at ever larger scales to develop. However, some challenging areas still remain where there is either a lack of atomic resolution structures or where the simulation system is inherentlycomplex.An area where both challenges are present is that of membranes containing membrane proteins. In this review we analyse a new practical approach to membrane protein study that offers a potential new route to high resolution structures and the possibility to simplify simulations.These new approaches collectively recognise that preservation of the interaction between the membrane protein and the lipid bilayer is often essential to maintain structure and function. The new methods preserve these interactions by producing nano-scale disc shaped particles that include bilayer and the chosen protein. Currently two approaches lead in this area: the MSP system that relies on peptides to stabilise the discs, and SMALPs where an amphipathic styrene maleic acid copolymer is used. Both methods greatly enable protein production and hence have the potential to accelerate atomic resolution structure determination as well as providing a simplified format for simulations of membrane protein dynamics.

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Section: Opportunity For Use In Molecular Simulationmentioning

confidence: 99%

Encapsulated membrane proteins: A simplified system for molecular simulation

Lee¹,

Khalid²,

Pollock³

et al. 2016

Biochimica et Biophysica Acta (BBA) - Biomembranes

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“…HPC system ARC1/ARC2 ARC1/ARC2 ARCHER Number of processors used 32 32 256 Speed (ns/day) ~1 ~1 ~5 acids, which are fast and user friendly [ 24 ]. Among the most popular open-source MD packages are AMBER [ 26 ], GROMACS [ 25 ], and NAMD [ 27 ].…”

Section: Introductionmentioning

confidence: 99%

“…Simulations of DNA minicircles require specialist high-performance computing facilities (HPC), such as the UK supercomputer ARCHER [ 24 ] or local HPC such as the University of Leeds supercomputers ARC1 and ARC2, where available. Running simulations in parallel over multiple CPU cores can effectively reduce the computing time.…”

Section: Introductionmentioning

confidence: 99%

Atomistic Molecular Dynamics Simulations of DNA Minicircle Topoisomers: A Practical Guide to Setup, Performance, and Analysis

Sutthibutpong

Noy

Harris

2016

Methods in Molecular Biology

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While DNA supercoiling is ubiquitous in vivo, the structure of supercoiled DNA is more challenging to study experimentally than simple linear sequences because the DNA must have a closed topology in order to sustain superhelical stress. DNA minicircles, which are closed circular double-stranded DNA sequences typically containing between 60 and 500 base pairs, have proven to be useful biochemical tools for the study of supercoiled DNA mechanics. We present detailed protocols for constructing models of DNA minicircles in silico, for performing atomistic molecular dynamics (MD) simulations of supercoiled minicircle DNA, and for analyzing the results of the calculations. These simulations are computationally challenging due to the large system sizes. However, improvements in parallel computing software and hardware promise access to improve conformational sampling and simulation timescales. Given the concurrent improvements in the resolution of experimental techniques such as atomic force microscopy (AFM) and cryo-electron microscopy, the study of DNA minicircles will provide a more complete understanding of both the structure and the mechanics of supercoiled DNA.

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“…Yet, at the molecular level, limitations to spatial and temporal resolution persist, and computer simulations are now employed routinely to complement insights from these experiments. [1][2][3] However, simulations of biomolecules, such as the ones carried out by integrating Newton's equations of motion, 4 are impaired by low scalability on general purpose hardware and by the rugged free energy landscape of atomistic models. 3,5 Interconversion rates between metastable states can be prohibitively low in conventional sampling (CS).…”

Section: Introductionmentioning

confidence: 99%

“…A seminal and well-known example in protein folding is found in the work of Pande et al 35 where energy variance is used as an indicator of large-scale transitions. The fundamental logic of adaptive sampling approaches can be described as follows: (1) simulations run, preferably in parallel, with an identical propagator, which is usually conventional MD; (2) information from the trajectories is collected and analyzed to determine which instantaneous conformations are most promising;…”

Section: Introductionmentioning

confidence: 99%

Focused conformational sampling in proteins

Bacci

Langini

Vymětal

et al. 2017

The Journal of Chemical Physics

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A detailed understanding of the conformational dynamics of biological molecules is difficult to obtain by experimental techniques due to resolution limitations in both time and space. Computer simulations avoid these in theory but are often too short to sample rare events reliably. Here we show that the progress index-guided sampling (PIGS) protocol can be used to enhance the sampling of rare events in selected parts of biomolecules without perturbing the remainder of the system. The method is very easy to use as it only requires as essential input a set of several features representing the parts of interest sufficiently. In this feature space, new states are discovered by spontaneous fluctuations alone and in unsupervised fashion. Because there are no energetic biases acting on phase space variables or projections thereof, the trajectories PIGS generates can be analyzed directly in the framework of transition networks. We demonstrate the possibility and usefulness of such focused explorations of biomolecules with two loops that are part of the binding sites of bromodomains, a family of epigenetic "reader" modules. This real-life application uncovers states that are structurally and kinetically far away from the initial crystallographic structures and are also metastable. Representative conformations are intended to be used in future high-throughput virtual screening campaigns.

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In pursuit of an accurate spatial and temporal model of biomolecules at the atomistic level: a perspective on computer simulation

Abstract: The current computational techniques available for biomolecular simulation are described, and the successes and limitations of each with reference to the experimental biophysical methods that they complement are presented.

Cited by 11 publications

References 52 publications

Encapsulated membrane proteins: A simplified system for molecular simulation

Encapsulated membrane proteins: A simplified system for molecular simulation

Atomistic Molecular Dynamics Simulations of DNA Minicircle Topoisomers: A Practical Guide to Setup, Performance, and Analysis

Focused conformational sampling in proteins

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