Tag Archives: modeling

Spatial-temporal models of protein structures

For a number of years I have been working on methods for validating computational models of structures [see ‘Model validation‘ on September 18th 2012] using the full potential of measurements made with modern techniques such as digital image correlation [see ‘256 shades of grey‘ on January 22nd 2014] and thermoelastic stress analysis [see ‘Counting photons to measure stress‘ on November 18th 2015].  Usually the focus of our interest is at the macroscale, for example the research on aircraft structures in the MOTIVATE project; however, in a new PhD project with colleagues at the National Tsing Hua University in Taiwan, we are planning to explore using our validation procedures and metrics [1] in structural biology.

The size and timescale of protein-structure thermal fluctuations are essential to the regulation of cellular functions. Measurement techniques such as x-ray crystallography and transmission electron cryomicroscopy (Cryo-EM) provide data on electron density distribution from which protein structures can be deduced using molecular dynamics models. Our aim is to develop our validation metrics to help identify, with a defined level of confidence, the most appropriate structural ensemble for a given set of electron densities. To make the problem more interesting and challenging the structure observed by x-ray crystallography is an average or equilibrium state because a folded protein is constantly in motion undergoing harmonic oscillations, each with different frequencies and amplitude [2].

The PhD project is part of the dual PhD programme of the University of Liverpool and National Tsing Hua University.  Funding is available in form of a fee waiver and contribution to living expenses for four years of study involving significant periods (perferably two years) at each university.  For more information follow this link.

References:

[1] Dvurecenska, K., Graham, S., Patelli, E. & Patterson, E.A., A probabilistic metric for the validation of computational models, Royal Society Open Society, 5:180687, 2018.

[2] Justin Chan, Hong-Rui Lin, Kazuhiro Takemura, Kai-Chun Chang, Yuan-Yu Chang, Yasumasa Joti, Akio Kitao, Lee-Wei Yang. An efficient timer and sizer of protein motions reveals the time-scales of functional dynamics in the ribosome (2018) https://www.biorxiv.org/content/early/2018/08/03/384511.

Image: A diffraction pattern and protein structure from http://xray.bmc.uu.se/xtal/

Models as fables

moel arthurIn his book, ‘Economic Rules – Why economics works, when it fails and how to tell the difference‘, Dani Rodrik describes models as fables – short stories that revolve around a few principal characters who live in an unnamed generic place and whose behaviour and interaction produce an outcome that serves as a lesson of sorts.  This seems to me to be a healthy perspective compared to the almost slavish belief in computational models that is common today in many quarters.  However, in engineering and increasingly in precision medicine, we use computational models as reliable and detailed predictors of the performance of specific systems.  Quantifying this reliability in a way that is useful to non-expert decision-makers is a current area of my research.  This work originated in aerospace engineering where it is possible, though expensive, to acquire comprehensive and information-rich data from experiments and then to validate models by comparing their predictions to measurements.  We have progressed to nuclear power engineering in which the extreme conditions and time-scales lead to sparse or incomplete data that make it more challenging to assess the reliability of computational models.  Now, we are just starting to consider models in computational biology where the inherent variability of biological data and our inability to control the real world present even bigger challenges to establishing model reliability.

Sources:

Dani Rodrik, Economic Rules: Why economics works, when it fails and how to tell the difference, Oxford University Press, 2015

Patterson, E.A., Taylor, R.J. & Bankhead, M., A framework for an integrated nuclear digital environment, Progress in Nuclear Energy, 87:97-103, 2016

Hack, E., Lampeas, G. & Patterson, E.A., An evaluation of a protocol for the validation of computational solid mechanics models, J. Strain Analysis, 51(1):5-13, 2016.

Patterson, E.A., Challenges in experimental strain analysis: interfaces and temperature extremes, J. Strain Analysis, 50(5): 282-3, 2015

Patterson, E.A., On the credibility of engineering models and meta-models, J. Strain Analysis, 50(4):218-220, 2015