Integrating an Enhanced Sampling Method and Small-Angle X-Ray Scattering to Study Intrinsically Disordered Proteins.

Chengtao Ding,Sheng Wang,Zhiyong Zhang

doi:10.3389/fmolb.2021.621128

Abstract

Intrinsically disordered proteins (IDPs) have been paid more and more attention over the past decades because they are involved in a multitude of crucial biological functions. Despite their functional importance, IDPs are generally difficult to investigate because they are very flexible and lack stable structures. Computer simulation may serve as a useful tool in studying IDPs. With the development of computer software and hardware, computational methods, such as molecular dynamics (MD) simulations, are popularly used. However, there is a sampling problem in MD simulations. In this work, this issue is investigated using an IDP called unique long region 11 (UL11), which is the conserved outer tegument component from herpes simplex virus 1. After choosing a proper force field and water model that is suitable for simulating IDPs, integrative modeling by combining an enhanced sampling method and experimental data like small-angle X-ray scattering (SAXS) is utilized to efficiently sample the conformations of UL11. The simulation results are in good agreement with experimental data. This work may provide a general protocol to study structural ensembles of IDPs.

Highlights

It has been recognized that a large segment of the human proteome comprises intrinsically disordered proteins (IDPs) that lack stable secondary and tertiary structures under physiological conditions (Colak et al, 2013; Kulkarni and Uversky, 2019)
In the first 70 ns of the accelerated MD (aMD) simulations, the protein is equilibrating with a clear tendency of radius of gyration (Rg) decrease (Figure 4A), and the Rg values essentially fluctuate between 21.0 and 27.5 Å in the remaining simulations
The aMD simulations at the time scale of 150 ns cannot adequately sample solution conformations of the IDP, which is the cause for the discrepancy between the simulated and the experimental pair distance distribution function (PDDF)

Summary

Introduction

It has been recognized that a large segment of the human proteome comprises intrinsically disordered proteins (IDPs) that lack stable secondary and tertiary structures under physiological conditions (Colak et al, 2013; Kulkarni and Uversky, 2019). IDPs play important roles in a multitude of crucial biological functions despite their lack of a stable structure, such as cell cycle regulation, molecular recognition, and signal transduction (Dunker et al, 2005; Uversky et al, 2005). Researchers continue to discover the functional importance of IDPs, it remains difficult to explore the structure-function relationship because getting the high-resolution structures of IDPs remains elusive. Since an IDP is generally not stable in one conformational state, these classical technologies of structural biology, including X-ray crystallography and cryo-EM, cannot determine its atomic-resolution structure. Structural information on the ensemble average of the Integrative Modeling of IDPs

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Conclusion