[3dem] Now Online: Frontiers in Cryo-EM Modeling

[Willy Wriggers]

Dear 3DEM community,

Our previously announced "Special Issue on Frontiers in Cryo-EM 
Modeling" has just been been published in the Journal of Chemical 
Information and Modeling at https://urldefense.com/v3/__https://pubs.acs.org/toc/jcisd8/60/5__;!!Mih3wA!UY38MwKzCLGc7gLHkVpzbdTbjFQ0mn5tCtl--c74igAh4PCEg-Zry1QaHJRICgcBdg$ .

The 26 contributions provide a timely benchmark in our research field. 
Below, please find a brief overview of relevant topics and senior 
authors (abridged from the editorial).

Thank you for your interest and happy reading!

Willy Wriggers (also on behalf of co-editors Giulia Palermo, Yuji 
Sugita, and Rommie E. Amaro).

---

Relating to a recent discussion on this list, Nobel laureate Joachim 
Frank contributed two papers on what has been informally called "cryoEM 
Dynamics" (see 3DEM forum messages on May 25 and 26, 2020). Several 
other perspectives on the value of contemporary cryoEM modeling include 
the potential impact of cryoEM in structure prediction approaches by 
Abriata and Dal Peraro, assessing the impact of computational modeling 
at the atomic level by Fraser, Lindorff-Larsen, and Bonomi, and how 
cryoEM stands to impact cellular-scale structural-omics type studies by 
McCafferty and colleagues. A review by Sengupta and coauthors covers 
advances in sample preparation and molecular modeling, whereas one by 
Ivanov and colleagues discusses recent advances and applications of 
flexible-fitting approaches for data refinement. Cossio discusses the 
need for and challenges related to cross-validation for developed 
models. Sanbonmatsu and colleagues, as well as Kellogg and Cianfrocco, 
present thoughtful contributions on potential cryoEM-modeling workflow 
pitfalls and best practices.

Methodological advances in integrative modeling cover a wide range of 
aspects and related experimental approaches. Wriggers and colleagues 
present a template-based deconvolution and denoising approach that 
corrects for missing wedge artifacts in tomograms of cytoskeletal 
filaments. Tama and co-workers present an in-depth look at pixel-size 
parameters for improving cryoEM maps. Winn and Joseph and colleagues 
demonstrate a novel method for calculating differences between a cryoEM 
map and a fitted model that uses amplitude matching in resolution 
shells, as well as show its utility in highlighting conformational and 
compositional differences. Cole and colleagues develop 
ImageDataExtractor, which identifies and extracts microscopy images from 
the scientific literature, presenting them for use in data-driven 
materials discovery-type approaches. Kihara and co-workers develop new 
software, MAINMASTseg, to improve map segmentation and results for 
cryoEM data sets with multiple chains. He and colleagues establish a 
cylindrical F1 score similarity metric for alpha-helices in cryoEM maps 
that provides a classifier for database validation studies as well as a 
criterion to assess the local quality of maps and their associated 
atomic models.

Several groups present new tools to improve the end-to-end cryoEM 
working procedures. Shen and co-workers present a fully automated 
toolkit, SPREAD, for 3D reconstruction that uses a network-based image 
clustering algorithm. Marabini and colleagues present a major update to 
their framework Scipion that improves model building and provenance of 
the complete workflow. Schenk and co-workers present CryoFLARE, an 
open-source platform for integrating various processing algorithms and 
development of automated workflows.

Molecular dynamics flexible fitting remains a popular approach for 
fitting atomic resolution models into density maps, as also reviewed by 
Ivanov and colleagues. A number of groups present extensions and 
improvements to the method. Lindert and Leelananda demonstrate how 
integrating NMR chemical shifts into cryoEM density restraints improves 
refinement results. Singharoy and co-workers present a new method that 
integrates neural network potentials together with quantum 
mechanical/molecular mechanics methods to improve on fitting small 
molecules into cryoEM maps. A related method presented by Costa and 
colleagues, MDeNM-EMfit, extends molecular dynamics with excited normal 
modes in a way that directs sampling toward conformations that have high 
correlations with the density maps.

Finally, several groups contributed applications to interesting 
biological systems. Magistrato and colleagues show how MD together with 
cryoEM provides never before seen insight into splicing modulators. 
Ravelli and co-workers show how processing algorithm improvements 
improved size limits for cryoEM using hen egg white lysozyme. Llorca and 
colleagues present their strategy for modeling the medium-density 
RUVBL2-binding domain, as well as subsequent simulations to explore 
biological hypotheses about its interactions with RNA polymerase II. 
Worrall and co-workers provide a historical perspective of cryoEM 
studies of the type III secretion system needle complex as well as 
describe their own workflow that enabled the successful determination of 
the whole complex.