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

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.

Molecular mechanism of specific HLA-A mRNA recognition by the RNA-binding-protein hMEX3B to promote tumor immune escape

“…After we obtained the above information about the binding patterns between hMEX3B and its RNA substrate, we tried to generate the structural model of the KH1/2-12-nt RNA by molecular dynamics (MD) simulation methods. Different from conventional MD simulation, integrative modeling combines an enhanced sampling method and experimental data such as SAXS to efficiently sample the conformations of the apo form and complex proteins 24 . During the simulation of the KH1/2 apo form, we found that χ2 decreases relatively fast in the first five cycles and then slowly converges to approximately 1.0 after the 5th cycle (Supplementary Fig.…”

Myofilament-associated proteins with intrinsic disorder (MAPIDs) and their resolution by computational modeling

“…3 ). However, extensive simulations and experimental techniques that are commonly used to probe IDRs ( Robustelli et al, 2020 ; Chang et al, 2021 ; Ding et al, 2021 ) are best suited for much smaller proteins. Therefore, many studies of intact MAPIDs are limited by the large number of disordered residues, as well as the likely presence of multiple disordered regions within a single protein.…”