Modeling Conformationally Flexible Proteins With X-ray Scattering and Molecular Simulations

• Published in: Computational and structural biotechnology journal Vol. 17; pp. 570 - 578
• Main Authors: Powers, Kyle T., Gildenberg, Melissa S., Washington, M. Todd
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-01-2019; Research Network of Computational and Structural Biotechnology; Elsevier
• Subjects: DNA polymerase; DNA replication; Minimal ensemble search; Protein structure; Review; SANS; SAXS; Dmax; DNA replication; BD; RPA; PCNA; SUMO; DNA polymerase; CG; SAXS; SEC; NMR; SANS; Rg; Cryo-EM; MD; LD; Minimal ensemble search; Protein structure; Pol η; LD, Langevin dynamics; Pol η, DNA polymerase eta; SAXS, small-angle X-ray scattering; RPA, replication protein A; Rg, radius of gyration; Dmax, maximal distance; MD, molecular dynamics; PCNA, proliferating cell nuclear antigen; SUMO, small ubiquitin-like modifie; SANS, small-angle neutron scattering; NMR, nuclear magnetic resonance; Cryo-EM, cryo-electron microscopy; SEC, size exclusion chromatography; BD, Brownian dynamics; CG, coarse-grained
• ISSN: 2001-0370; 2001-0370
• DOI: 10.1016/j.csbj.2019.04.011

Proteins and protein complexes with high conformational flexibility participate in a wide range of biological processes. These processes include genome maintenance, gene expression, signal transduction, cell cycle regulation, and many others. Gaining a structural understanding of conformationally flexible proteins and protein complexes is arguably the greatest problem facing structural biologists today. Over the last decade, some progress has been made toward understanding the conformational flexibility of such systems using hybrid approaches. One particularly fruitful strategy has been the combination of small-angle X-ray scattering (SAXS) and molecular simulations. In this article, we provide a brief overview of SAXS and molecular simulations and then discuss two general approaches for combining SAXS data and molecular simulations: minimal ensemble approaches and full ensemble approaches. In minimal ensemble approaches, one selects a minimal ensemble of structures from the simulations that best fit the SAXS data. In full ensemble approaches, one validates a full ensemble of structures from the simulations using SAXS data. We argue that full ensemble models are more realistic than minimal ensemble searches models and that full ensemble approaches should be used wherever possible.
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•Conformationally flexible proteins are a major challenge for structural biologists.•Flexible proteins can be examined by combining molecular simulations and SAXS.•Minimal ensemble searches are a common way of combining simulations and SAXS.•Full ensemble methods use SAXS to validate simulations without curve fitting.•Full ensemble models are more realistic than minimal ensemble searches models.