Recent Force Field Strategies for Intrinsically Disordered Proteins

Abstract

Intrinsically disordered proteins (IDPs) are widely distributed across eukaryotic cells, playing important roles in molecular recognition, molecular assembly, post-translational modification, and other biological processes. IDPs are also associated with many diseases such as cancers, cardiovascular diseases, and neurodegenerative diseases. Due to their structural flexibility, conventional experimental methods cannot reliably capture their heterogeneous structures. Molecular dynamics simulation becomes an important complementary tool to quantify IDP structures. This review covers recent force field strategies proposed for more accurate molecular dynamics simulations of IDPs. The strategies include adjusting dihedral parameters, adding grid-based energy correction map (CMAP) parameters, refining protein–water interactions, and others. Different force fields were found to perform well on specific observables of specific IDPs but also are limited in reproducing all available experimental observables consistently for all tested IDPs. We conclude the review with perspective areas for improvements for future force fields for IDPs.

Advanced Sampling Methods for Multiscale Simulation of Disordered Proteins and Dynamic Interactions

“…To achieve this, it is also critical to develop suitable water models and better describe the water-protein interactions [52,53]. Two recent review articles have already provided comprehensive descriptions on the latest development of better protein force fields [51,54]. We therefore briefly summarize the state-of-the-art of nonpolarizable and polarizable force fields for IDP dynamics and interactions.…”

“…These problems were likely attributed to the unbalanced parameterization of dihedral torsion space and the description of protein-protein and protein-water interactions [56]. As a result, most of the improved force fields managed to give more accurate secondary structure propensities by adjusting dihedral parameters or adding grid-based energy correction map (CMAP) parameters [54]. The over-compactness of disordered proteins can be alleviated by modifying protein-water van der Waals interactions or combining with refined water models [52].…”

An Overview of Several Inhibitors for Alzheimer’s Disease: Characterization and Failure

“…Researchers have strived hard to develop perfect FFs to improve IDPs description; they aim to describe the high flexibility of these proteins, thus enlarging the conformational ensemble and increase the possibility of locating them in different local minima. Mu et al [ 36 ] reported a couple of ideas to improve the accuracy of FFs for IDPs structural characterization, (1) Modification of force field parameters aided by global optimization, and (2) Maintaining a good balance between secondary structure via reparameterization (backbone dihedral parameters and vdW interaction between water-protein interaction) of existing FFs. One of the most common problems among the IDPs force field is over-stabilizing protein-protein interaction that impacts the aggregation mechanism of IDPs.…”

“…One of the most common problems among the IDPs force field is over-stabilizing protein-protein interaction that impacts the aggregation mechanism of IDPs. Due to the IDPs force field’s inaccuracy, Mu et al [ 36 ] encouraged improving backbone dihedral parameters and Lennard-Jones potential parameter (protein-water interaction) in the existing IDPs FFs and obtained training data from experimental observation and quantum chemical calculation. Undoubtedly, both reparameterization and training strategies may assist in new FFs development.…”

Energetics of a protein disorder-order transition in small molecule recognition

“…Consequently there is an unmet need for methodologies that facilitate the design of modulators of disorder-to-order transition in protein structures. [19][20][21][22][23][24][25][26] With the view of advancing general understanding of small molecule-IDR interactions, the present report focuses on elucidating the energetics of a disorder-to-order transition mechanism observed upon binding of the small molecule AM-7209 to the N-terminal domain of the MDM2 protein (Figure 1A,1B). MDM2 is a negative regulator of the tumor suppressor p53.…”