Abstract

A growing array of experimental techniques allows us to characterize the three-dimensional structure of large biological assemblies at increasingly higher resolution. In addition to X-ray crystallography and nuclear magnetic resonance in solution, new structure determination methods such cryo-electron microscopy (cryo-EM), crosslinking/mass spectrometry and solid-state NMR have emerged. Often it is not sufficient to use a single experimental method, but complementary data need to be collected by using multiple techniques. The integration of all datasets can only be achieved by computational means. This article describes Inferential structure determination, a Bayesian approach to integrative modeling of biomolecular complexes with hybrid structural data. I will introduce probabilistic models for cryo-EM maps and outline Markov chain Monte Carlo algorithms for sampling model structures from the posterior distribution. I will focus on rigid and flexible modeling with cryo-EM data and discuss some of the computational challenges of Bayesian inference in the context of biomolecular modeling.

Highlights

  • Thanks to groundbreaking advances in experimental techniques it has become possible to study the structure of large biological assemblies at increasingly higher resolution

  • Highresolution biomolecular structure determination was only possible by X-ray crystallography or nuclear magnetic resonance (NMR) in solution (Berman et al, 2000)

  • Inferential structure determination (ISD) was developed for solution NMR data on small protein domains (Rieping et al, 2008; Habeck, 2012)

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Summary

Introduction

Thanks to groundbreaking advances in experimental techniques it has become possible to study the structure of large biological assemblies at increasingly higher resolution. Several biologically essential assemblies that resisted high-resolution studies have recently been characterized by cryo-EM including spliceosomal complexes (Yan et al, 2015; Agafonov et al, 2016; Galej et al, 2016; Rauhut et al, 2016; Wan et al, 2016), eukaryotic ribosomes (Anger et al, 2013; Khatter et al, 2015), and transcription initiation complexes (Plaschka et al, 2015)

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