Adaptive BXD in multi-dimensional CV space


We’ve recently published a paper describing some nice extensions to the “boxed molecular dynamics” (BXD) rare event method (open-access draft available here). BXD is a method that I’ve been working on for the last few years for accelerating rare events in chemical simulations (there’s a 1-d implementation available in the CHARMM package).

The underlying BXD idea is straightforward: assuming I have a chemical transformation that I want to study, and some sense of the collective variables (CVs) that are important along the transformation pathway, I can splice the CV space into a set of ‘boxes’. A “box” is defined as a region of configuration space that lies between two boundaries; within any given box, a trajectory runs on a potential energy surface which is unmodified. If the trajectory crosses a particular box boundary, a velocity inversion operation is performed to keep it within the specified box. BXD simulations are run by locking the system within a set of adjacent ‘boxes’, and then performing statistical analysis of the time spent in the each box, and the relative number of hits at the boundaries which define the box. These quantities define box-to-box rate coefficients, which can then be used to calculate a potential of mean force, which is independent of the boundary locations. Choosing BXD boundaries is analogous to the process of specifying umbrellas (in umbrella sampling). A key difference is the fact that umbrella sampling requires two parameters per umbrella (location and force constant); whereas BXD requires only one parameter (location). With the appropriate set of boxes, it is possible to sample spaces that otherwise have a low probability of being populated.

In our recent paper, we made two useful developments to BXD. We showed that BXD can be: (1) utilized to explore multi-dimensional CV spaces, and (2) formulated in a fashion that enables adaptive exploration of minimum free energy pathways. The video shows BXD adaptively sampling reactive pathways for deuterium transfer between a Fluorine radical and deuterated acetonitrile solvent molecules.  Specifically, we told BXD to adaptively sample the free energy pathway in a 2d CV space (the D–F distance and the C–D distance).

Unlike umbrella sampling or metadynamics, BXD does not bias the underlying potential energy surface of a given system. As a result, it can be shown within certain limits that the BXD dynamics correspond to the “real” system dynamics. The philosophy that guides the adaptive BXD algorithm is therefore very simple: by ‘listening’ to the system dynamics, we get an idea of where the system is trying to go, and are therefore able to adaptively locate box boundaries which nudge the system along so that it does not become trapped. The video in fact shows the box boundaries which BXD places as it ‘listens’ to the system dynamics.

tying molecular knots in virtual reality

Over the past few months, I’ve been playing with a new integrated hardware-software framework that fuses the latest in interactive high-performance computing, the latest in virtual reality, and the latest in research-grade GPU-accelerated molecular physics. It’s really fun, and I’m basically addicted. Since we got it working, I’ve had a steady stream of colleagues knocking on my office door asking me if they can try it out. It’s slightly annoying, because I had intended to be ultra-productive during the summer lull in the academic calendar, but that has hasn’t really worked out… When my colleagues aren’t playing with it, then I’ve struggled to get much work done because I’ve mostly spent time hanging out in VR playing with my favourite molecular simulations…

The video demos a virtual reality port of the Nano Simbox, (aka “Simbox”), a tool which I’ve been developing over the years in collaboration with Bristol-based software firm iSci (aka Interactive Scientific). It lets us manipulate entirely rigorous molecular dynamics simulations (run on a massively parallel high-performance computing back-end) in real-time. We’re just now starting to explore application domains for this technology. The video in this post shows one of our first experiments: in a collaborative project carried out with artist & lecturer Becca Rose, we used the VR-Simbox to tie knots in large molecules: proteins, polyenes, and DNA. The extent to which biomolecular structures form knots is in fact an active research domain (nicely outlined in this Nature perspective by Eugene Shahknovich); many scientists have spent time trying to understand the extent to which nature utilizes knotted topologies.

Knotting is an interesting application for the VR Simbox, because the manipulations required to tie a knot in a large molecular structure like a protein are actually pretty complex. For example, if I was going to write some code to tie a molecular knot, it would end up being a rather complicated little piece of software. However, tying knots is the sort of thing that’s actually rather straightforward and intuitive for a human, because we all tie knots all the time (and the sailors and knitters amongst us are even more expert). It’s a good example of how a human working with a computer can actually accomplish things faster than a computer on its own. Over the next few months, we’ll be building a molecular virtual reality lab right here in Bristol, so stay tuned…



“Tust Forest” courtesy of Prof Eric Heller

Richard Feynmann famously said “If we were to name the most powerful assumption of all, which leads one on and on in an attempt to understand life, it is that all things are made of atoms, and that everything that living things do can be understood in terms of the jigglings and wigglings of atoms.

As somebody who spends his life worrying about molecular dynamics, this statement certainly rings true for me, and lots of my colleagues. Along these lines, myself and Dr. Basile Curchod recently worked with Richard Bright to co-edit a special issue of Interalia (an online hybrid arts magazine), focused on the topic of “micro-choreography”. The aim was to highlight examples where aesthetic practice draws inspiration from the molecular sciences and also ways in which molecular science draws on aesthetics to create representations of nature which are invisible to our eyes. You can read excerpts from the Interalia micro-choreography issue here; if don’t have full access through your institutional affiliation, then you should email Richard Bright, who will set you up with a 3-month trial subscription to access all of Interalia’s content.

We brought together a fantastic set of contributors for the issue, including practicing artists (Luke JerramGünes-Hélène Isitan, and Lisa May Thomas) and also academics (Prof Eric Heller [Harvard], David S. Goodsell [Scripps], Drew Berry [Melbourne], and Simon Park [Surrey]). We also had an image contest: our favourite submissions are published in the Micro-choreography gallery, with contributions from Florian Stroehl, Ljiljana Fruk, Ula Alexander, Susanna Monti, Craig Russell, and Becca Rose.

I’m excited about this issue. Not only is it extremely rich in aesthetic content, but it also aligns with my growing interests over the last few years in a domain I’ve started calling ‘the aesthetics of scientific imagination’ – i.e., the “design” decisions entailed in scientific visualization of the invisible dynamics of nature. This is particularly important in tiny domains which cannot be seen with the naked eye, because our scientific intuition is guided by the aesthetic representations we use to imagine phenomena which are otherwise invisible. In fact I would almost go so far to claim that imagery is the reality in these domains, profoundly impacting how we communicate these ‘realities’, in both research & educational contexts.

My hope is that this “micro-choreography” issue will provide inspiration for people to think about how aesthetic enquiry and scientific enquiry can engage in mutual dialogue, with each pushing the other another into new territories.

Leonardo Cover Article


Just a quick post here to highlight some exciting news: we’ve got a paper on the cover of the current issue of Leonardo – and it looks lovely! Leonardo, published by MIT press, is the leading international peer-reviewed journal on the use of contemporary science and technology in the arts and music, and also for discussing applications and influences of the arts and humanities on science and technology.

I’m excited about this paper. danceroom Spectroscopy (dS) and Hidden Fields have been going strong since 2012, and have now been experienced by over 100,000 people across Europe, Asia, and the USA. We’ve had several exciting opportunities and invitations for installations and performances at a range of interesting & prestigious venues around the world, including the London 2012 Olympics, the ZKM | Centre for Art and Media Technology in Karlsruhe, the Barbican in London, Austria’s Ars Electronica, the Salzburg festival, New York’s World Science festival, Stanford University’s art institute, and even the Bhutan international arts festival in Thimphu.

To date, the papers which have come out from this work have focused primarily on the technological aspects – e.g., on the GPU-accelerated computing algorithms, or the underlying molecular physics. But this Leonardo paper provided a format where we were free to articulate many of the artistic observations that we’ve made during the dS & Hidden fields development process. This opportunity for artistic reflection was something I really enjoyed; the last time I wrote a paper for a more arts & humanities audience was back in 2010 (too long ago!) – and I found the process of writing for Leonardo a really refreshing change of pace!

The arts & creative technology side of our research has actually had a brilliant stretch recently: March also saw publication of a paper entitled “Evolving Atomic Aesthetics and Dynamics“. It was presented at the Evostar 2016 conference on bio-inspired computing, where it received a nomination for “best paper”.

The citations to both of these papers are as follows:

T. Mitchell, J. Hyde, P. Tew, and D. R. Glowacki, “danceroom Spectroscopy: At the Frontiers of Physics, Performance, Interactive Art and Technology”, Leonardo, 49(2), 138 (2016).

T. Mitchell, P. Tew, J. Smith, D.R. Glowacki, “Interactively Evolving Atomic Aesthetics and Dynamics”, vol 9596 (Evolutionary and Biologically Inspired Music, Sound, Art and Design), Lecture Notes in Computer Science, vol 9596, 17 – 30

ICOMET & 峨眉山 (Éméi Shān)


the map that got me up & down Emei Shan (click for high-res)

I’ve been meaning to post this for awhile, but it got away from me. Last October (2015!) I had the privilege of attending the ICOMET (International Conference on Molecular Energy Transfer) in Chengdu (Sichuan province, China). Organized by Prof. Aart Kleijn, the meeting was hosted by the Chinese academy of Engineering Physics and the Chinese Academy of Sciences. It covered a wide range of topics, including experimental and theoretical topics in energy transfer across the gas phase, gas/surface scattering, liquid phases, astrochemistry, and biochemistry. The meeting organization was flawless and the treatment we received from our Chinese hosts was extremely generous.


bank, central Chengdu

Chengdu, capital of Sichuan province (Sichuan means ‘four rivers’), has an interesting history. The Chengdu region has been inhabited for at least 4000 years, and it has existed with the place-name “Chengdu” for over 2000 years. Wikipedia lists its population as 14m, but our Chinese hosts consistently cited populationfigures closer to 20m. The ICOMET meeting kept me busy, but I had the opportunity for a little exploration. I visited the former home of Du Fu (one of the Tang dynasty’s most noted poets); I saw some of the antique markets in central Chengdu; and I also had the chance to sample a hot-pot & some mapo tofu. These days, Chengdu is a polluted and crowded megacity; it sort of scared the shit out of me, and made me properly wonder where all this free-market consumption is leading our species. On one occasion I happened to stroll into a suburban shopping mall where they had a four-story aquarium containing four massive whale-sharks, which you could glance at while you browsed for Nikes and ate your McDonald’s.

After the meeting finished, I took an extra few days and made my way to 峨眉山 (transliterated as “Éméi Shān”; translated as “Mt. Emei”), essentially the gateway to the Himalayas – about two hours west of Chengdu via bullet train. Éméi Shān is one of China’s four Holy Buddhist mountains, with an elevation of about 3100 meters. It’s a holy beacon that draws Chinese tourists from all over, but most folks cluster at one of two places: (1) the temples at Éméi Shān’s base; or (2) the golden summit (there’s a bus/cable car combo to get the top if you’d rather not walk). If you choose to walk, then you find yourself alone the moment you set out on the path and start climbing, which is exactly what you want on Éméi Shān. As much as Chengdu frightened me,  Éméi Shān comforted me: it’s where I met face-to-face the full force of classical China in all her glory – and Good God, Lord have Mercy!

It’s a solid 12-14 hour day walking up to the summit, and a slightly shorter day back down. An ancient Buddhist pilgrimage route that dates from the first century C.E., the entire path up Éméi Shān is hand-laid: tens of thousands of individual stone steps. The path is dotted with more than 70 ancient temples, each of which seamlessly blends into that little bit of mountain where it has resided for centuries. On approach, many of the temples seemed to quietly emerge out of the sub-tropical mist that bathed the mountain. Every temple had a shrine room where visitors could make prayers and offerings. Each shrine room was full of some of the most amazing artworks I’ve ever seen – statues, mandalas, thangkas, textiles… In many of the temples, it was possible to wander around the entire place freely. Most of the temples are actively tended by monks, who kept the fires and incense burning. Many even offered tea or a small cell where pilgrims could sleep on their journey to the summit. There’s also monkeys on the path – and they’re aggressive little buggers if they think you might have something they want. I was warned to carry a bamboo stick just in case, and it was good advice (I had a rather edgy encounter on account of an orange that I was casually peeling during descent).

A massive four-headed golden statue of Samantabhadra buddha sits at Éméi Shān’s summit, with the high Himalayas off to the West. At sunrise, the mountain weather patterns are such that that Éméi Shān’s summit often pokes just above the clouds, allowing you to see what the Chinese call the ‘cloud sea’. Samantabhadra is positioned so that his head catches the rising sun from the East and glory scatters, casting a rainbow-ringed shadow onto the cloud sea below… Absolutely amazing. Éméi Shān is one sacred place that I sincerely hope I have the good fortune to revisit again at some point in my life.



around the world in 26 days


From 6th Dec 2016 – 31st Dec 2016, I managed a proper global circumnavigation: London -> Thailand -> Indonesia -> Hawaii -> Portland -> Milwaukee -> Boston -> London. It was all down to a series of meetings that clicked into place at the last second – a good example of how disorganised procrastination can sometimes work for good. Had I conscientiously organised any individual part of the journey in advance, the entire trip wouldn’t have been possible. So I’m chalking this one up to the benefit to leaving things till the last second, and trusting the universe to sort out the details.

In Thailand and Indonesia, I was invited to participate in two Royal Society Symposia on Computational Chemistry – one at Chulalongkorn University in Bangkok, and the other at Institut Teknologi Bandung on the island of Java. Designed to forge links between scientists in the developed world and scientists in the developing world, these symposia provided fascinating insight into a range of computational chemistry applications. Most interesting to me was the extent to which computational chemistry was coupled to urgent issues in each country. For example, several of the Thai scientists were using comp chem to design drugs for combatting various strains of avian flu. Several of the Indonesian scientists were using computational chemistry to analyse the efficiency with which different materials capture solar energy. Or to characterise palm natural product extracts. Or to understand the water filtration efficiency of volcanic zeolites.

In Hawaii, I attended the Pacifichem conference, where I presented some stuff I’ve been working on with Dr. Basile Curchod (who recently found out he was awarded a Marie Curie fellowship!) aimed at developing a non-adiabatic transition state theory for understanding the non-adiabatic and excited state dynamics that arise following photo-excitation in atmospheric oxidation intermediates.

I then visited my brother in Portland for a few days; and then onto Milwaukee to see my family for Christmas; and then onto Boston to visit a friend at MIT, and finally back to London.

It was an amazing trip. During the Indonesian leg, I managed to tack on a few extra days to explore the former sultanate of Yogyakarta and the surrounding countryside. I hired a motorbike and dove into the [insane] Yogyakarta traffic. I visited Mount Merapi, an active volcano just north of Yogyakarta which last erupted in 2010. I also visited the Buddhist holy site at Borobudur, a temple whose top level has 72 Buddhas, all enclosed in upside-down lotus flower stupas with their hands in the Dharmachakra mudra. I also went to the Hindu holy site at Prambanan, to visit a majestic temple that honours the three manifestations of God within the holy Trimurti – Brahma (Creator), Vishnu (Preserver), and Shiva (destroyer/transformer).


Reactive Dynamics Tutorial

As part of the virtual Winterschool on Computational Chemistry, I gave a presentation outlining the methods that we’ve been developing over the past few years which enable folks to carry out reactive dynamics using the multi-state empirical valence bond (MS-EVB) method. Taking advantage of the fact that I could deliver the virtual lecture from the comfort of my own command line, I took the opportunity to guide viewers through a tutorial on how to use the MS-EVB functionality that we’ve implemented within a branch of the TINKER molecular dynamics package that I initiated with Jeremy Harvey a few years ago. This project, which is hosted on SourceForge and available for download, is effectively an OpenMPI parallelized version of TINKER, which is molecular dynamics package distributed by Jay Ponder’s lab at Washington University in St. Louis. I regularly get email requests from folks who are studying reaction dynamics asking to use this stuff, so I have included video links to the presentation in case they are of use to others. The presentation is in two parts:

Part 1 outlines the types of systems that we have studied to date using our MS-EVB reactive dynamics codes, and a brief discussion of some of the insights and results from that work.

Part 2 describes how to build the MPI-parallelized version of TINKER, along with several examples of how to run it. These include: geometry optimizations (TS & minima), frequency calculations, single point energy calculations, and an NVE molecular dynamics simulation.