Studies on Molecular Dynamics of Intrinsically Disordered Proteins and Their Fuzzy Complexes: A Mini-Review

The molecular dynamics (MD) method is a promising approach toward elucidating the molecular mechanisms of intrinsically disordered regions (IDRs) of proteins and their fuzzy complexes. This mini-review introduces recent studies that apply MD simulations to investigate the molecular recognition of IDRs. Firstly, methodological issues by which MD simulations treat IDRs, such as developing force fields, treating periodic boundary conditions, and enhanced sampling approaches, are discussed. Then, several examples of the applications of MD to investigate molecular interactions of IDRs in terms of the two kinds of complex formations; coupled-folding and binding and fuzzy complex. MD simulations provide insight into the molecular mechanisms of these binding processes by sampling conformational ensembles of flexible IDRs. In particular, we focused on all-atom explicit-solvent MD simulations except for studies of higher-order assembly of IDRs. Recent advances in MD methods, and computational power make it possible to dissect the molecular details of realistic molecular systems involving the dynamic behavior of IDRs.

[1]  L. Garrett-Sinha,et al.  Cellular and Molecular Life Sciences Review of Ets1 Structure, Function, and Roles in Immunity , 2022 .

[2]  Takeshi Kawabata,et al.  Multimodal Structural Distribution of the p53 C-Terminal Domain upon Binding to S100B via a Generalized Ensemble Method: From Disorder to Extradisorder. , 2019, Journal of chemical theory and computation.

[3]  So Much More to Know … , 2005, Science.

[4]  Y. Nishimura,et al.  The neural repressor NRSF/REST binds the PAH1 domain of the Sin3 corepressor by using its distinct short hydrophobic helix. , 2005, Journal of molecular biology.

[5]  Takuya Takahashi,et al.  Assessment of dynamic properties of water around a monovalent ion: A classical molecular dynamics simulation study , 2011 .

[6]  M. Otyepka,et al.  Explicit Water Models Affect the Specific Solvation and Dynamics of Unfolded Peptides While the Conformational Behavior and Flexibility of Folded Peptides Remain Intact. , 2010, Journal of chemical theory and computation.

[7]  Haruki Nakamura,et al.  myPresto/omegagene: a GPU-accelerated molecular dynamics simulator tailored for enhanced conformational sampling methods with a non-Ewald electrostatic scheme , 2016, Biophysics and physicobiology.

[8]  Wookyung Yu,et al.  Benchmarking all-atom simulations using hydrogen exchange , 2014, Proceedings of the National Academy of Sciences.

[9]  A. Mark,et al.  Convergence and sampling efficiency in replica exchange simulations of peptide folding in explicit solvent. , 2007, The Journal of chemical physics.

[10]  J. Martí,et al.  A molecular dynamics simulation study of hydrogen bonding in aqueous ionic solutions , 2005 .

[11]  Kengo Kinoshita,et al.  Protein informatics towards function identification. , 2003, Current opinion in structural biology.

[12]  Haruki Nakamura,et al.  The worldwide Protein Data Bank (wwPDB): ensuring a single, uniform archive of PDB data , 2006, Nucleic Acids Res..

[13]  K. Dill,et al.  The Protein-Folding Problem, 50 Years On , 2012, Science.

[14]  Parbati Biswas,et al.  Diffusion of Hydration Water around Intrinsically Disordered Proteins. , 2015, The journal of physical chemistry. B.

[15]  Marie Skepö,et al.  Molecular Dynamics Simulations of Intrinsically Disordered Proteins: On the Accuracy of the TIP4P-D Water Model and the Representativeness of Protein Disorder Models. , 2016, Journal of chemical theory and computation.

[16]  Dong Song,et al.  The IDP-Specific Force Field ff14IDPSFF Improves the Conformer Sampling of Intrinsically Disordered Proteins , 2017, J. Chem. Inf. Model..

[17]  Michael R Sawaya,et al.  Structural Studies of Amyloid Proteins at the Molecular Level. , 2017, Annual review of biochemistry.

[18]  Wenwei Zheng,et al.  Temperature-Controlled Liquid–Liquid Phase Separation of Disordered Proteins , 2019, ACS central science.

[19]  Stefano Piana,et al.  Assessing the accuracy of physical models used in protein-folding simulations: quantitative evidence from long molecular dynamics simulations. , 2014, Current opinion in structural biology.

[20]  H. Dyson,et al.  Intrinsically unstructured proteins: re-assessing the protein structure-function paradigm. , 1999, Journal of molecular biology.

[21]  Daniel J. Sindhikara,et al.  Exchange frequency in replica exchange molecular dynamics. , 2008, The Journal of chemical physics.

[22]  Joan-Emma Shea,et al.  Simulations of disordered proteins and systems with conformational heterogeneity. , 2017, Current opinion in structural biology.

[23]  Kresten Lindorff-Larsen,et al.  Evaluating the Effects of Cutoffs and Treatment of Long-range Electrostatics in Protein Folding Simulations , 2012, PloS one.

[24]  M. Madan Babu,et al.  The contribution of intrinsically disordered regions to protein function, cellular complexity, and human disease , 2016, Biochemical Society transactions.

[25]  Wenwei Zheng,et al.  Sequence determinants of protein phase behavior from a coarse-grained model , 2017, bioRxiv.

[26]  D. Svergun,et al.  Kirkwood-Buff Approach Rescues Overcollapse of a Disordered Protein in Canonical Protein Force Fields. , 2015, The journal of physical chemistry. B.

[27]  M. Blackledge,et al.  Binding Mechanisms of Intrinsically Disordered Proteins: Theory, Simulation, and Experiment , 2016, Front. Mol. Biosci..

[28]  Marc S. Cortese,et al.  Analysis of molecular recognition features (MoRFs). , 2006, Journal of molecular biology.

[29]  R. Pappu,et al.  A Molecular Grammar Governing the Driving Forces for Phase Separation of Prion-like RNA Binding Proteins , 2018, Cell.

[30]  A. Kidera,et al.  Multicanonical Ensemble Generated by Molecular Dynamics Simulation for Enhanced Conformational Sampling of Peptides , 1997 .

[31]  Rohit V Pappu,et al.  CAMELOT: A machine learning approach for coarse-grained simulations of aggregation of block-copolymeric protein sequences. , 2015, The Journal of chemical physics.

[32]  R. Pappu,et al.  Conformational preferences and phase behavior of intrinsically disordered low complexity sequences: insights from multiscale simulations. , 2019, Current opinion in structural biology.

[33]  S. Phillpot,et al.  Exact method for the simulation of Coulombic systems by spherically truncated, pairwise r−1 summation , 1999 .

[34]  J. Mccammon,et al.  Molecular Dynamics Simulations of a Polyalanine Octapeptide under Ewald Boundary Conditions: Influence of Artificial Periodicity on Peptide Conformation , 2000 .

[35]  Jianhan Chen.  Intrinsically Disordered p53 Extreme C-Terminus Binds to S100B(ββ) through “Fly-Casting” , 2009 .

[36]  P. Biswas,et al.  Local Structure and Dynamics of Hydration Water in Intrinsically Disordered Proteins. , 2015, The journal of physical chemistry. B.

[37]  Wenwei Zheng,et al.  Relation between single-molecule properties and phase behavior of intrinsically disordered proteins , 2018, Proceedings of the National Academy of Sciences.

[38]  Haruki Nakamura,et al.  Density functional study of molecular interactions in secondary structures of proteins , 2016, Biophysics and physicobiology.

[39]  S. Showalter,et al.  Atomistic simulations reveal structural disorder in the RAP74-FCP1 complex. , 2011, The journal of physical chemistry. B.

[40]  Ikuo Fukuda,et al.  Zero-multipole summation method for efficiently estimating electrostatic interactions in molecular system. , 2013, The Journal of chemical physics.

[41]  Y. Sugita,et al.  Replica-exchange molecular dynamics method for protein folding , 1999 .

[42]  Marie Skepö,et al.  Molecular Dynamics Simulations of Intrinsically Disordered Proteins: Force Field Evaluation and Comparison with Experiment. , 2015, Journal of chemical theory and computation.

[43]  Haruki Nakamura,et al.  A Novel Approach of Dynamic Cross Correlation Analysis on Molecular Dynamics Simulations and Its Application to Ets1 Dimer–DNA Complex , 2014, PloS one.

[44]  Colin K Kitakawa,et al.  Hydrogen bond donors and acceptors are generally depolarized in α‐helices as revealed by a molecular tailoring approach , 2019, bioRxiv.

[45]  Haruki Nakamura,et al.  A free-energy landscape for coupled folding and binding of an intrinsically disordered protein in explicit solvent from detailed all-atom computations. , 2011, Journal of the American Chemical Society.

[46]  Thomas M Truskett,et al.  Structural ensemble of an intrinsically disordered polypeptide. , 2013, The journal of physical chemistry. B.

[47]  Orsolya Gereben,et al.  On the accurate calculation of the dielectric constant from molecular dynamics simulations: The case of SPC/E and SWM4-DP water , 2011 .

[48]  Haruki Nakamura,et al.  Enhanced and effective conformational sampling of protein molecular systems for their free energy landscapes , 2012, Biophysical Reviews.

[49]  Haruki Nakamura,et al.  Molecular mechanisms of cooperative binding of transcription factors Runx1–CBFβ–Ets1 on the TCRα gene enhancer , 2017, PloS one.

[50]  Paul Robustelli,et al.  Water dispersion interactions strongly influence simulated structural properties of disordered protein states. , 2015, The journal of physical chemistry. B.

[51]  Srinivasaraghavan Kannan,et al.  Long range recognition and selection in IDPs: the interactions of the C-terminus of p53 , 2016, Scientific Reports.

[52]  Peter J Rossky,et al.  A simple atomic-level hydrophobicity scale reveals protein interfacial structure. , 2014, Journal of molecular biology.

[53]  Nicolas L. Fawzi,et al.  Protein Phase Separation: A New Phase in Cell Biology. , 2018, Trends in cell biology.

[54]  P. P. Ewald.  Die Berechnung optischer und elektrostatischer Gitterpotentiale , 1921 .

[55]  Haruki Nakamura,et al.  Outcome of the First wwPDB Hybrid/Integrative Methods Task Force Workshop. , 2015, Structure.

[56]  I. Fukuda,et al.  Enhanced Sampling of Molecular Dynamics Simulations of a Polyalanine Octapeptide: Effects of the Periodic Boundary Conditions on Peptide Conformation. , 2018, The journal of physical chemistry. B.

[57]  A. Cavalli,et al.  Structural and Kinetic Characterization of the Intrinsically Disordered Protein SeV NTAIL through Enhanced Sampling Simulations. , 2017, The journal of physical chemistry. B.

[58]  E. Fadda,et al.  The transient manifold structure of the p53 extreme C-terminal domain: insight into disorder, recognition, and binding promiscuity by molecular dynamics simulations. , 2017, Physical chemistry chemical physics : PCCP.

[59]  C. Anfinsen.  Principles that govern the folding of protein chains. , 1973, Science.

[60]  Daniel J. Sindhikara,et al.  Exchange Often and Properly in Replica Exchange Molecular Dynamics. , 2010, Journal of chemical theory and computation.

[61]  D. Koshland.  The Key–Lock Theory and the Induced Fit Theory , 1995 .

[62]  Robert B. Best,et al.  A Preformed Binding Interface in the Unbound Ensemble of an Intrinsically Disordered Protein: Evidence from Molecular Simulations , 2012, PLoS Comput. Biol..

[63]  Jinghai Li,et al.  Simulation of coupled folding and binding of an intrinsically disordered protein in explicit solvent with metadynamics. , 2016, Journal of molecular graphics & modelling.

[64]  B. L. de Groot,et al.  Structural Ensembles of Intrinsically Disordered Proteins Depend Strongly on Force Field: A Comparison to Experiment. , 2015, Journal of chemical theory and computation.

[65]  Takuya Takahashi,et al.  Influence of various parameters in the replica-exchange molecular dynamics method: Number of replicas, replica-exchange frequency, and thermostat coupling time constant , 2018, Biophysics and physicobiology.

[66]  Haruki Nakamura,et al.  The zero-multipole summation method for estimating electrostatic interactions in molecular dynamics: analysis of the accuracy and application to liquid systems. , 2014, The Journal of chemical physics.

[67]  Mark J Abraham,et al.  Ensuring Mixing Efficiency of Replica-Exchange Molecular Dynamics Simulations. , 2008, Journal of chemical theory and computation.

[68]  T. Inoue-Bungo,et al.  A novel allosteric mechanism on protein-DNA interactions underlying the phosphorylation-dependent regulation of Ets1 target gene expressions. , 2015, Journal of molecular biology.

[69]  H. Chan,et al.  Coarse-grained residue-based models of disordered protein condensates: utility and limitations of simple charge pattern parameters. , 2018, Physical chemistry chemical physics : PCCP.

[70]  R. Tycko,et al.  Structure of FUS Protein Fibrils and Its Relevance to Self-Assembly and Phase Separation of Low-Complexity Domains , 2017, Cell.

[71]  Junichi Higo,et al.  Enhanced sampling simulations to construct free-energy landscape of protein–partner substrate interaction , 2015, Biophysical Reviews.

[72]  H. Kamberaj,et al.  Correlated motions and interactions at the onset of the DNA-induced partial unfolding of Ets-1. , 2009, Biophysical journal.

[73]  Monika Fuxreiter,et al.  Fuzziness in Protein Interactions-A Historical Perspective. , 2018, Journal of molecular biology.

[74]  Xavier Daura,et al.  Molecular dynamics simulations of a reversibly folding beta-heptapeptide in methanol: influence of the treatment of long-range electrostatic interactions. , 2009, The journal of physical chemistry. B.

[75]  S. Metallo,et al.  Targeting Intrinsically Disordered Transcription Factors: Changing the Paradigm. , 2018, Journal of molecular biology.

[76]  A. Doxey,et al.  Novel function discovery through sequence and structural data mining. , 2016, Current opinion in structural biology.

[77]  P. Tompa,et al.  Fuzzy complexes: polymorphism and structural disorder in protein-protein interactions. , 2008, Trends in biochemical sciences.

[78]  M. Parrinello,et al.  Anomalous water diffusion in salt solutions , 2014, Proceedings of the National Academy of Sciences.

[79]  K. Lindorff-Larsen,et al.  How robust are protein folding simulations with respect to force field parameterization? , 2011, Biophysical journal.

[80]  Charles Seife,et al.  What Is the Universe Made Of? , 2005, Science.

[81]  Haruki Nakamura,et al.  Non-Ewald methods: theory and applications to molecular systems , 2012, Biophysical Reviews.

[82]  Paul Robustelli,et al.  Developing a molecular dynamics force field for both folded and disordered protein states , 2018, Proceedings of the National Academy of Sciences.

[83]  L. McIntosh,et al.  Synergy of aromatic residues and phosphoserines within the intrinsically disordered DNA-binding inhibitory elements of the Ets-1 transcription factor , 2014, Proceedings of the National Academy of Sciences.

[84]  Aleksandra Karolak,et al.  Importance of local interactions for the stability of inhibitory helix 1 in apo Ets-1. , 2012, Biophysical chemistry.

[85]  Haruki Nakamura,et al.  Phosphorylation of an intrinsically disordered region of Ets1 shifts a multi-modal interaction ensemble to an auto-inhibitory state , 2018, Nucleic acids research.

[86]  Stefan Wallin,et al.  Binding of Two Intrinsically Disordered Peptides to a Multi-Specific Protein: A Combined Monte Carlo and Molecular Dynamics Study , 2012, PLoS Comput. Biol..

[87]  H. Okumura,et al.  Oligomer Formation of Amyloid-β(29-42) from Its Monomers Using the Hamiltonian Replica-Permutation Molecular Dynamics Simulation. , 2016, The journal of physical chemistry. B.

[88]  Marcos A. Villarreal,et al.  On the Ewald Artifacts in Computer Simulations. The Test-Case of the Octaalanine Peptide With Charged Termini , 2005, Journal of biomolecular structure & dynamics.

[89]  Nicolas L. Fawzi,et al.  Phosphorylation of the FUS low‐complexity domain disrupts phase separation, aggregation, and toxicity , 2017, The EMBO journal.

[90]  Santi Esteban-Martín,et al.  Progress in studying intrinsically disordered proteins with atomistic simulations. , 2015, Progress in biophysics and molecular biology.

[91]  Wenning Wang,et al.  Extreme Fuzziness: Direct Interactions between Two IDPs , 2019, Biomolecules.

[92]  Haruki Nakamura,et al.  Variation of free‐energy landscape of the p53 C‐terminal domain induced by acetylation: Enhanced conformational sampling , 2016, J. Comput. Chem..

[93]  P. Jemth,et al.  A structurally heterogeneous transition state underlies coupled binding and folding of disordered proteins , 2018, The Journal of Biological Chemistry.

[94]  R. Nussinov,et al.  Folding and binding cascades: shifts in energy landscapes. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[95]  Yu Li,et al.  The Dynamic Multisite Interactions between Two Intrinsically Disordered Proteins. , 2017, Angewandte Chemie.

[96]  B. L. de Groot,et al.  CHARMM36m: an improved force field for folded and intrinsically disordered proteins , 2016, Nature Methods.

[97]  R. Best,et al.  Balanced Protein–Water Interactions Improve Properties of Disordered Proteins and Non-Specific Protein Association , 2014, Journal of chemical theory and computation.

[98]  Monika Fuxreiter,et al.  Fold or not to fold upon binding - does it really matter? , 2019, Current opinion in structural biology.

[99]  Haruki Nakamura,et al.  Conformational Ensembles of an Intrinsically Disordered Protein pKID with and without a KIX Domain in Explicit Solvent Investigated by All-Atom Multicanonical Molecular Dynamics , 2012, Biomolecules.

[100]  Katrine Bugge,et al.  Extreme disorder in an ultrahigh-affinity protein complex , 2018, Nature.

[101]  A. Roitberg,et al.  Structured and Unstructured Binding of an Intrinsically Disordered Protein as Revealed by Atomistic Simulations. , 2016, Journal of the American Chemical Society.

[102]  W. J. Allen,et al.  Modeling the relationship between the p53 C-terminal domain and its binding partners using molecular dynamics. , 2010, The journal of physical chemistry. B.

[103]  Gerhard Hummer,et al.  Error and efficiency of replica exchange molecular dynamics simulations. , 2009, The Journal of chemical physics.

[104]  R. Best.  Computational and theoretical advances in studies of intrinsically disordered proteins. , 2017, Current opinion in structural biology.

[105]  T. Head-Gordon,et al.  Optimizing solute-water van der Waals interactions to reproduce solvation free energies. , 2012, The journal of physical chemistry. B.