Advances in the Molecular Dynamics Flexible Fitting Method for Cryo-EM Modeling

Overview

Journal Methods

Specialty Biochemistry

Date 2016 Jan 26

PMID 26804562

Citations 49

Authors

Ryan McGreevy

Ivan Teo

Abhishek Singharoy

Klaus Schulten

Affiliations

Soon will be listed here.

Abstract

Molecular Dynamics Flexible Fitting (MDFF) is an established technique for fitting all-atom structures of molecules into corresponding cryo-electron microscopy (cryo-EM) densities. The practical application of MDFF is simple but requires a user to be aware of and take measures against a variety of possible challenges presented by each individual case. Some of these challenges arise from the complexity of a molecular structure or the limited quality of available structural models and densities to be interpreted, while others stem from the intricacies of MDFF itself. The current article serves as an overview of the strategies that have been developed since MDFF's inception to overcome common challenges and successfully perform MDFF simulations.

Citing Articles

A structural biology compatible file format for atomic force microscopy.

Jiang Y, Wang Z, Scheuring S Nat Commun. 2025; 16(1):1671.

PMID: 39955301 PMC: 11829953. DOI: 10.1038/s41467-025-56760-7.

The structure of apolipoprotein B100 from human low-density lipoprotein.

Berndsen Z, Cassidy C Nature. 2024; 638(8051):836-843.

PMID: 39662503 PMC: 11839476. DOI: 10.1038/s41586-024-08467-w.

MDFF_NM: Improved Molecular Dynamics Flexible Fitting into Cryo-EM Density Maps with a Multireplica Normal Mode-Based Search.

Dahmani Z, Scott A, Venien-Bryan C, Perahia D, Costa M J Chem Inf Model. 2024; 64(13):5151-5160.

PMID: 38907694 PMC: 11234365. DOI: 10.1021/acs.jcim.3c02007.

Cryo-EM structure and B-factor refinement with ensemble representation.

Beton J, Mulvaney T, Cragnolini T, Topf M Nat Commun. 2024; 15(1):444.

PMID: 38200043 PMC: 10781738. DOI: 10.1038/s41467-023-44593-1.

Enhancing cryo-EM maps with 3D deep generative networks for assisting protein structure modeling.

Maddhuri Venkata Subramaniya S, Terashi G, Kihara D Bioinformatics. 2023; 39(8).

PMID: 37549063 PMC: 10444963. DOI: 10.1093/bioinformatics/btad494.

References

Singharoy A, Venkatakrishnan B, Liu Y, Mayne C, Lee S, Chen C . Macromolecular Crystallography for Synthetic Abiological Molecules: Combining xMDFF and PHENIX for Structure Determination of Cyanostar Macrocycles. J Am Chem Soc. 2015; 137(27):8810-8. PMC: 4504762. DOI: 10.1021/jacs.5b04407. View

Scheres S, Chen S . Prevention of overfitting in cryo-EM structure determination. Nat Methods. 2012; 9(9):853-4. PMC: 4912033. DOI: 10.1038/nmeth.2115. View

. IUPAC-IUB Commission on Biochemical Nomenclature. Abbreviations and symbols for the description of the conformation of polypeptide chains. J Mol Biol. 1970; 52(1):1-17. View

Kudryashev M, Wang R, Brackmann M, Scherer S, Maier T, Baker D . Structure of the type VI secretion system contractile sheath. Cell. 2015; 160(5):952-962. PMC: 4359589. DOI: 10.1016/j.cell.2015.01.037. View

Schlitter J, Engels M, Kruger P . Targeted molecular dynamics: a new approach for searching pathways of conformational transitions. J Mol Graph. 1994; 12(2):84-9. DOI: 10.1016/0263-7855(94)80072-3. View

Gumbart J, Trabuco L, Schreiner E, Villa E, Schulten K . Regulation of the protein-conducting channel by a bound ribosome. Structure. 2009; 17(11):1453-64. PMC: 2778611. DOI: 10.1016/j.str.2009.09.010. View

Lasker K, Forster F, Bohn S, Walzthoeni T, Villa E, Unverdorben P . Molecular architecture of the 26S proteasome holocomplex determined by an integrative approach. Proc Natl Acad Sci U S A. 2012; 109(5):1380-7. PMC: 3277140. DOI: 10.1073/pnas.1120559109. View

Adams P, Afonine P, Bunkoczi G, Chen V, Echols N, Headd J . The Phenix software for automated determination of macromolecular structures. Methods. 2011; 55(1):94-106. PMC: 3193589. DOI: 10.1016/j.ymeth.2011.07.005. View

Villa E, Sengupta J, Trabuco L, LeBarron J, Baxter W, Shaikh T . Ribosome-induced changes in elongation factor Tu conformation control GTP hydrolysis. Proc Natl Acad Sci U S A. 2009; 106(4):1063-8. PMC: 2613361. DOI: 10.1073/pnas.0811370106. View

10.

Trabuco L, Villa E, Schreiner E, Harrison C, Schulten K . Molecular dynamics flexible fitting: a practical guide to combine cryo-electron microscopy and X-ray crystallography. Methods. 2009; 49(2):174-80. PMC: 2753685. DOI: 10.1016/j.ymeth.2009.04.005. View

11.

Li W, Trabuco L, Schulten K, Frank J . Molecular dynamics of EF-G during translocation. Proteins. 2011; 79(5):1478-86. PMC: 3132869. DOI: 10.1002/prot.22976. View

12.

Lindert S, McCammon J . Improved cryoEM-Guided Iterative Molecular Dynamics--Rosetta Protein Structure Refinement Protocol for High Precision Protein Structure Prediction. J Chem Theory Comput. 2015; 11(3):1337-46. PMC: 4393324. DOI: 10.1021/ct500995d. View

13.

Jabs A, Weiss M, Hilgenfeld R . Non-proline cis peptide bonds in proteins. J Mol Biol. 1999; 286(1):291-304. DOI: 10.1006/jmbi.1998.2459. View

14.

Stone J, McGreevy R, Isralewitz B, Schulten K . GPU-accelerated analysis and visualization of large structures solved by molecular dynamics flexible fitting. Faraday Discuss. 2014; 169:265-83. PMC: 4208074. DOI: 10.1039/c4fd00005f. View

15.

Kucukelbir A, Sigworth F, Tagare H . Quantifying the local resolution of cryo-EM density maps. Nat Methods. 2013; 11(1):63-5. PMC: 3903095. DOI: 10.1038/nmeth.2727. View

16.

Bharat T, Castillo Menendez L, Hagen W, Lux V, Igonet S, Schorb M . Cryo-electron microscopy of tubular arrays of HIV-1 Gag resolves structures essential for immature virus assembly. Proc Natl Acad Sci U S A. 2014; 111(22):8233-8. PMC: 4050629. DOI: 10.1073/pnas.1401455111. View

17.

Chan K, Trabuco L, Schreiner E, Schulten K . Cryo-electron microscopy modeling by the molecular dynamics flexible fitting method. Biopolymers. 2012; 97(9):678-86. PMC: 3376020. DOI: 10.1002/bip.22042. View

18.

Henderson R, Sali A, Baker M, Carragher B, Devkota B, Downing K . Outcome of the first electron microscopy validation task force meeting. Structure. 2012; 20(2):205-14. PMC: 3328769. DOI: 10.1016/j.str.2011.12.014. View

19.

McGreevy R, Singharoy A, Li Q, Zhang J, Xu D, Perozo E . xMDFF: molecular dynamics flexible fitting of low-resolution X-ray structures. Acta Crystallogr D Biol Crystallogr. 2014; 70(Pt 9):2344-55. PMC: 4157446. DOI: 10.1107/S1399004714013856. View

20.

Humphrey W, Dalke A, Schulten K . VMD: visual molecular dynamics. J Mol Graph. 1996; 14(1):33-8, 27-8. DOI: 10.1016/0263-7855(96)00018-5. View