Molecular simulations of IDPs: From ensemble generation to IDP interactions leading to disorder-to-order transitions

Fatafta, Hebah; Samantray, Suman; Sayyed-Ahmad, Abdallah; Coskuner‐Weber, Orkid; Strodel, Birgit

doi:10.1016/bs.pmbts.2021.06.003

Cited by 12 publications

(17 citation statements)

References 200 publications

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“…AA force field parameters specifically aimed at solving these issues have been developed, targeting either backbone torsional behavior or protein−water van der Waals interactions. 337,338 The use of specific potential energy terms, as explored by UNRES and AWSEM, brings an additional challenge not shared by the other CG approaches mentioned in this Review: the need for an MD engine supporting model-specific features. Although UNRES and AWSEM clearly show the benefits in computational performance that this strategy can bring, the need to provide long-term software support (such as porting the code to different hardware, e.g., GPU, and operating systems) obligates the developers to also dedicate constant effort in these directions.…”

Section: Perspectivesmentioning

confidence: 99%

Pragmatic Coarse-Graining of Proteins: Models and Applications

Borges-Araújo,

Patmanidis,

Singh

et al. 2023

J. Chem. Theory Comput.

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The molecular details involved in the folding, dynamics, organization, and interaction of proteins with other molecules are often difficult to assess by experimental techniques. Consequently, computational models play an ever-increasing role in the field. However, biological processes involving large-scale protein assemblies or long time scale dynamics are still computationally expensive to study in atomistic detail. For these applications, employing coarse-grained (CG) modeling approaches has become a key strategy. In this Review, we provide an overview of what we call pragmatic CG protein models, which are strategies combining, at least in part, a physics-based implementation and a top-down experimental approach to their parametrization. In particular, we focus on CG models in which most protein residues are represented by at least two beads, allowing these models to retain some degree of chemical specificity. A description of the main modern pragmatic protein CG models is provided, including a review of the most recent applications and an outlook on future perspectives in the field.

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Section: Perspectivesmentioning

confidence: 99%

Pragmatic Coarse-Graining of Proteins: Models and Applications

Borges-Araújo,

Patmanidis,

Singh

et al. 2023

J. Chem. Theory Comput.

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show abstract

“…With limited information, experimental methods struggle to capture detailed IDP conformations, while computational methods, including all‐atom simulations and coarse‐grained models, compensate for this shortcoming to some extent. Empirical force fields for proteins were originally developed to simulate folded structures which do not perform well to sample disordered structures 54,55 . In recent years, with the growing interest in IDPs, IDP‐specific and useable force fields have been developed.…”

Section: The Dynamic Structures Of Idpsmentioning

confidence: 99%

“…In recent years, with the growing interest in IDPs, IDP‐specific and useable force fields have been developed. General strategies applied include 54–58 (1) adjusting backbone dihedral parameters through training force fields with additional dihedral data from the coil structures in the PDB to balance propensities of secondary structures; (2) adding grid‐based energy correction map (CMAP) to reduce potential energy surface discrepancies between quantum mechanical/experimental data and simulated ones based on the distribution of φ/ψ dihedral angles; (3) refining protein–water interactions to avoid overly compact IDP structures; (4) using residue‐specific parameters to better reflect residues' conformational preferences.…”

Section: The Dynamic Structures Of Idpsmentioning

confidence: 99%

“…This signifies the necessity of integrating computational and experimental approaches to understand IDP dynamic structures and interactions and calls for the development of a universal force field for all types of proteins. For a detailed summary of the development strategies and evaluations of IDP force fields, interested readers are encouraged to refer to recent in‐depth and comprehensive review articles 54–56 …”

Section: The Dynamic Structures Of Idpsmentioning

confidence: 99%

“…Although MD simulations can provide atomic‐level conformational information for IDPs, they are limited by sampling efficacy and high computational cost. Various enhanced sampling methods have been developed 55,70 . More recently, deep learning‐based enhanced sampling and trajectory analysis methods have emerged 29,71,72 …”

Section: The Dynamic Structures Of Idpsmentioning

confidence: 99%

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Rational drug design targeting intrinsically disordered proteins

Wang,

Xiong,

Lai

2023

WIREs Comput Mol Sci

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Intrinsically disordered proteins (IDPs) are proteins that perform important biological functions without well‐defined structures under physiological conditions. IDPs can form fuzzy complexes with other molecules, participate in the formation of membraneless organelles, and function as hubs in protein–protein interaction networks. The malfunction of IDPs causes major human diseases. However, drug design targeting IDPs remains challenging due to their highly dynamic structures and fuzzy interactions. Turning IDPs into druggable targets provides a great opportunity to extend the druggable target‐space for novel drug discovery. Integrative structural biology approaches that combine information derived from computational simulations, artificial intelligence/data‐driven analysis and experimental studies have been used to uncover the dynamic structures and interactions of IDPs. An increasing number of ligands that directly bind IDPs have been found either by target‐based experimental and computational screening or phenotypic screening. Along with the understanding of IDP binding with its partners, structure‐based drug design strategies, especially conformational ensemble‐based computational ligand screening and computer‐aided ligand optimization algorithms, have greatly accelerated the development of IDP ligands. It is inspiring that several IDP‐targeting small‐molecule and peptide drugs have advanced into clinical trials. However, new computational methods need to be further developed for efficiently discovering and optimizing specific and potent ligands for the vast number of IDPs. Along with the understanding of their dynamic structures and interactions, IDPs are expected to become valuable treasure of drug targets.This article is categorized under: Structure and Mechanism > Computational Biochemistry and Biophysics

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A brief history of amyloid aggregation simulations

Fatafta,

Khaled,

Kav

et al. 2024

WIREs Comput Mol Sci

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Amyloid proteins are characterized by their tendency to aggregate into amyloid fibrils, which are often associated with devastating diseases. Aggregation pathways typically involve unfolding or misfolding of monomeric proteins and formation of transient oligomers and protofibrils before the final aggregation product is formed. The conformational dynamics and polymorphic and volatile nature of these aggregation intermediates make their characterization by experimental techniques alone insufficient and also require computational approaches. Over the past 25 years, the size of simulated amyloid aggregation systems and the length of these simulations have increased significantly. These advances are discussed here. The review includes simulation approaches that model the aggregating peptides or proteins at both the all‐atom and coarse‐grained levels, use molecular dynamics simulations or Monte Carlo sampling to simulate the conformational changes, and present results for various amyloid peptides and proteins ranging from Lys‐Phe‐Phe‐Glu (KFFE) as the smallest system to as an intermediate‐sized peptide to α‐synuclein. The presentation of the history of amyloid aggregation simulations concludes with a discussion of where the future of these simulations may lie.This article is categorized under: Structure and Mechanism > Computational Biochemistry and Biophysics Molecular and Statistical Mechanics > Molecular Dynamics and Monte‐Carlo Methods

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Molecular simulations of IDPs: From ensemble generation to IDP interactions leading to disorder-to-order transitions

Cited by 12 publications

References 200 publications

Pragmatic Coarse-Graining of Proteins: Models and Applications

Pragmatic Coarse-Graining of Proteins: Models and Applications

Rational drug design targeting intrinsically disordered proteins

A brief history of amyloid aggregation simulations

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