skip to main content
DOE PAGES title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Improved Modeling of Peptide-Protein Binding Through Global Docking and Accelerated Molecular Dynamics Simulations

Abstract

We find that peptides mediate up to 40% of known protein-protein interactions in higher eukaryotes and play a key role in cellular signaling, protein trafficking, immunology, and oncology. However, it is challenging to predict peptide-protein binding with conventional computational modeling approaches, due to slow dynamics and high peptide flexibility. Here, we present a prototype of the approach which combines global peptide docking using ClusPro PeptiDock and all-atom enhanced simulations using Gaussian accelerated molecular dynamics (GaMD). For three distinct model peptides, the lowest backbone root-mean-square deviations (RMSDs) of their bound conformations relative to X-ray structures obtained from PeptiDock were 3.3–4.8 Å, being medium quality predictions according to the Critical Assessment of PRediction of Interactions (CAPRI) criteria. GaMD simulations refined the peptide-protein complex structures with significantly reduced peptide backbone RMSDs of 0.6–2.7 Å, yielding two high quality (sub-angstrom) and one medium quality models. Furthermore, the GaMD simulations identified important low-energy conformational states and revealed the mechanism of peptide binding to the target proteins. Therefore, PeptiDock+GaMD is a promising approach for exploring peptide-protein interactions.

Authors:
 [1];  [2];  [2];  [1]
  1. Univ. of Kansas, Lawrence, KS (United States)
  2. Stony Brook Univ., NY (United States). Laufer Center for Physical and Quantitative Biology
Publication Date:
Research Org.:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States). National Energy Research Scientific Computing Center (NERSC)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1577835
Grant/Contract Number:  
AC02-05CH11231
Resource Type:
Accepted Manuscript
Journal Name:
Frontiers in Molecular Biosciences
Additional Journal Information:
Journal Volume: 6; Journal ID: ISSN 2296-889X
Publisher:
Frontiers Media SA
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Wang, Jinan, Alekseenko, Andrey, Kozakov, Dima, and Miao, Yinglong. Improved Modeling of Peptide-Protein Binding Through Global Docking and Accelerated Molecular Dynamics Simulations. United States: N. p., 2019. Web. doi:10.3389/fmolb.2019.00112.
Wang, Jinan, Alekseenko, Andrey, Kozakov, Dima, & Miao, Yinglong. Improved Modeling of Peptide-Protein Binding Through Global Docking and Accelerated Molecular Dynamics Simulations. United States. doi:10.3389/fmolb.2019.00112.
Wang, Jinan, Alekseenko, Andrey, Kozakov, Dima, and Miao, Yinglong. Wed . "Improved Modeling of Peptide-Protein Binding Through Global Docking and Accelerated Molecular Dynamics Simulations". United States. doi:10.3389/fmolb.2019.00112. https://www.osti.gov/servlets/purl/1577835.
@article{osti_1577835,
title = {Improved Modeling of Peptide-Protein Binding Through Global Docking and Accelerated Molecular Dynamics Simulations},
author = {Wang, Jinan and Alekseenko, Andrey and Kozakov, Dima and Miao, Yinglong},
abstractNote = {We find that peptides mediate up to 40% of known protein-protein interactions in higher eukaryotes and play a key role in cellular signaling, protein trafficking, immunology, and oncology. However, it is challenging to predict peptide-protein binding with conventional computational modeling approaches, due to slow dynamics and high peptide flexibility. Here, we present a prototype of the approach which combines global peptide docking using ClusPro PeptiDock and all-atom enhanced simulations using Gaussian accelerated molecular dynamics (GaMD). For three distinct model peptides, the lowest backbone root-mean-square deviations (RMSDs) of their bound conformations relative to X-ray structures obtained from PeptiDock were 3.3–4.8 Å, being medium quality predictions according to the Critical Assessment of PRediction of Interactions (CAPRI) criteria. GaMD simulations refined the peptide-protein complex structures with significantly reduced peptide backbone RMSDs of 0.6–2.7 Å, yielding two high quality (sub-angstrom) and one medium quality models. Furthermore, the GaMD simulations identified important low-energy conformational states and revealed the mechanism of peptide binding to the target proteins. Therefore, PeptiDock+GaMD is a promising approach for exploring peptide-protein interactions.},
doi = {10.3389/fmolb.2019.00112},
journal = {Frontiers in Molecular Biosciences},
number = ,
volume = 6,
place = {United States},
year = {2019},
month = {10}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record

Save / Share:

Works referenced in this record:

Investigating allosteric effects on the functional dynamics of β2-adrenergic ternary complexes with enhanced-sampling simulations
journal, January 2017

  • Saleh, Noureldin; Saladino, Giorgio; Gervasio, Francesco Luigi
  • Chemical Science, Vol. 8, Issue 5
  • DOI: 10.1039/C6SC04647A

An unexpected switch in peptide binding mode: from simulation to substrate specificity
journal, November 2017

  • Kahler, Ursula; Fuchs, Julian E.; Goettig, Peter
  • Journal of Biomolecular Structure and Dynamics, Vol. 36, Issue 15
  • DOI: 10.1080/07391102.2017.1407674

Computational techniques for efficient conformational sampling of proteins
journal, April 2008

  • Liwo, Adam; Czaplewski, Cezary; Ołdziej, Stanisław
  • Current Opinion in Structural Biology, Vol. 18, Issue 2
  • DOI: 10.1016/j.sbi.2007.12.001

Nonphysical sampling distributions in Monte Carlo free-energy estimation: Umbrella sampling
journal, February 1977


Position of Transmembrane Helix 6 Determines Receptor G Protein Coupling Specificity
journal, July 2014

  • Rose, Alexander S.; Elgeti, Matthias; Zachariae, Ulrich
  • Journal of the American Chemical Society, Vol. 136, Issue 32
  • DOI: 10.1021/ja5055109

On searching in, sampling of, and dynamically moving through conformational space of biomolecular systems: A review
journal, January 2007

  • Christen, Markus; van Gunsteren, Wilfred F.
  • Journal of Computational Chemistry, Vol. 29, Issue 2
  • DOI: 10.1002/jcc.20725

re-TAMD: exploring interactions between H3 peptide and YEATS domain using enhanced sampling
journal, April 2018


Enhanced Sampling in Molecular Dynamics Using Metadynamics, Replica-Exchange, and Temperature-Acceleration
journal, December 2013


Characterizing the conformational landscape of MDM2-binding p53 peptides using Molecular Dynamics simulations
journal, November 2017


Generalized-ensemble algorithms: enhanced sampling techniques for Monte Carlo and molecular dynamics simulations
journal, May 2004


Gaussian Accelerated Molecular Dynamics: Unconstrained Enhanced Sampling and Free Energy Calculation
journal, July 2015

  • Miao, Yinglong; Feher, Victoria A.; McCammon, J. Andrew
  • Journal of Chemical Theory and Computation, Vol. 11, Issue 8
  • DOI: 10.1021/acs.jctc.5b00436

AnchorDock: Blind and Flexible Anchor-Driven Peptide Docking
journal, May 2015


Comparison of simple potential functions for simulating liquid water
journal, July 1983

  • Jorgensen, William L.; Chandrasekhar, Jayaraman; Madura, Jeffry D.
  • The Journal of Chemical Physics, Vol. 79, Issue 2
  • DOI: 10.1063/1.445869

CAPRI: A Critical Assessment of PRedicted Interactions
journal, May 2003

  • Janin, Jo�l; Henrick, Kim; Moult, John
  • Proteins: Structure, Function, and Genetics, Vol. 52, Issue 1
  • DOI: 10.1002/prot.10381

Protein-peptide association kinetics beyond the seconds timescale from atomistic simulations
journal, October 2017


ClusPro PeptiDock: efficient global docking of peptide recognition motifs using FFT
journal, April 2017


Molecular Basis of Ligand Dissociation in β-Adrenergic Receptors
journal, September 2011


Metadynamics: a method to simulate rare events and reconstruct the free energy in biophysics, chemistry and material science
journal, November 2008


GalaxyPepDock: a protein–peptide docking tool based on interaction similarity and energy optimization
journal, May 2015

  • Lee, Hasup; Heo, Lim; Lee, Myeong Sup
  • Nucleic Acids Research, Vol. 43, Issue W1
  • DOI: 10.1093/nar/gkv495

How T cell receptors interact with peptide-MHCs: A multiple steered molecular dynamics study
journal, August 2011

  • Cuendet, Michel A.; Zoete, Vincent; Michielin, Olivier
  • Proteins: Structure, Function, and Bioinformatics, Vol. 79, Issue 11
  • DOI: 10.1002/prot.23104

A Unified Conformational Selection and Induced Fit Approach to Protein-Peptide Docking
journal, March 2013


CABS-dock web server for the flexible docking of peptides to proteins without prior knowledge of the binding site
journal, May 2015

  • Kurcinski, Mateusz; Jamroz, Michal; Blaszczyk, Maciej
  • Nucleic Acids Research, Vol. 43, Issue W1
  • DOI: 10.1093/nar/gkv456

Differences between G-Protein-Stabilized Agonist-GPCR Complexes and their Nanobody-Stabilized Equivalents
journal, July 2017

  • Saleh, Noureldin; Ibrahim, Passainte; Clark, Timothy
  • Angewandte Chemie International Edition, Vol. 56, Issue 31
  • DOI: 10.1002/anie.201702468

Gaussian Accelerated Molecular Dynamics in NAMD
journal, December 2016

  • Pang, Yui Tik; Miao, Yinglong; Wang, Yi
  • Journal of Chemical Theory and Computation, Vol. 13, Issue 1
  • DOI: 10.1021/acs.jctc.6b00931

Backbone-dependent Rotamer Library for Proteins Application to Side-chain Prediction
journal, March 1993

  • Dunbrack, Roland L.; Karplus, Martin
  • Journal of Molecular Biology, Vol. 230, Issue 2
  • DOI: 10.1006/jmbi.1993.1170

PIPER: An FFT-based protein docking program with pairwise potentials
journal, August 2006

  • Kozakov, Dima; Brenke, Ryan; Comeau, Stephen R.
  • Proteins: Structure, Function, and Bioinformatics, Vol. 65, Issue 2
  • DOI: 10.1002/prot.21117

DARS (Decoys As the Reference State) Potentials for Protein-Protein Docking
journal, November 2008


PepBind: A Comprehensive Database and Computational Tool for Analysis of Protein–peptide Interactions
journal, August 2013

  • Das, Arindam Atanu; Sharma, Om Prakash; Kumar, Muthuvel Suresh
  • Genomics, Proteomics & Bioinformatics, Vol. 11, Issue 4
  • DOI: 10.1016/j.gpb.2013.03.002

Importance of the Force Field Choice in Capturing Functionally Relevant Dynamics in the von Willebrand Factor
journal, March 2019

  • Kuzmanic, Antonija; Pritchard, Ruth B.; Hansen, D. Flemming
  • The Journal of Physical Chemistry Letters, Vol. 10, Issue 8
  • DOI: 10.1021/acs.jpclett.9b00517

Molecular Simulations Identify Binding Poses and Approximate Affinities of Stapled α-Helical Peptides to MDM2 and MDMX
journal, January 2017

  • Morrone, Joseph A.; Perez, Alberto; Deng, Qiaolin
  • Journal of Chemical Theory and Computation, Vol. 13, Issue 2
  • DOI: 10.1021/acs.jctc.6b00978

Structural Analysis Identifies Imidazo[1,2- b ]Pyridazines as PIM Kinase Inhibitors with In vitro Antileukemic Activity
journal, July 2007


Exploring Protein-Peptide Recognition Pathways Using a Supervised Molecular Dynamics Approach
journal, April 2017


Rosetta FlexPepDock ab-initio: Simultaneous Folding, Docking and Refinement of Peptides onto Their Receptors
journal, April 2011


A Comprehensive Review on Current Advances in Peptide Drug Development and Design
journal, May 2019

  • Lee, Andy Chi-Lung; Harris, Janelle Louise; Khanna, Kum Kum
  • International Journal of Molecular Sciences, Vol. 20, Issue 10
  • DOI: 10.3390/ijms20102383

Accelerated molecular dynamics: A promising and efficient simulation method for biomolecules
journal, June 2004

  • Hamelberg, Donald; Mongan, John; McCammon, J. Andrew
  • The Journal of Chemical Physics, Vol. 120, Issue 24
  • DOI: 10.1063/1.1755656

MDockPeP: An ab-initio protein-peptide docking server : MDockPeP: An
journal, October 2018

  • Xu, Xianjin; Yan, Chengfei; Zou, Xiaoqin
  • Journal of Computational Chemistry, Vol. 39, Issue 28
  • DOI: 10.1002/jcc.25555

PepX: a structural database of non-redundant protein–peptide complexes
journal, October 2009

  • Vanhee, Peter; Reumers, Joke; Stricher, Francois
  • Nucleic Acids Research, Vol. 38, Issue suppl_1
  • DOI: 10.1093/nar/gkp893

Thermodynamics and kinetics simulations of multi-time-scale processes for complex systems
journal, April 2008

  • Gao, Yi Qin; Yang, Lijiang; Fan, Yubo
  • International Reviews in Physical Chemistry, Vol. 27, Issue 2
  • DOI: 10.1080/01442350801920334

ff14SB: Improving the Accuracy of Protein Side Chain and Backbone Parameters from ff99SB
journal, July 2015

  • Maier, James A.; Martinez, Carmenza; Kasavajhala, Koushik
  • Journal of Chemical Theory and Computation, Vol. 11, Issue 8
  • DOI: 10.1021/acs.jctc.5b00255

Improved Reweighting of Accelerated Molecular Dynamics Simulations for Free Energy Calculation
journal, May 2014

  • Miao, Yinglong; Sinko, William; Pierce, Levi
  • Journal of Chemical Theory and Computation, Vol. 10, Issue 7
  • DOI: 10.1021/ct500090q

Peptide therapeutics: current status and future directions
journal, January 2015


Rapid, Precise, and Reproducible Prediction of Peptide–MHC Binding Affinities from Molecular Dynamics That Correlate Well with Experiment
journal, June 2015

  • Wan, Shunzhou; Knapp, Bernhard; Wright, David W.
  • Journal of Chemical Theory and Computation, Vol. 11, Issue 7
  • DOI: 10.1021/acs.jctc.5b00179

Umbrella sampling: Umbrella sampling
journal, May 2011

  • Kästner, Johannes
  • Wiley Interdisciplinary Reviews: Computational Molecular Science, Vol. 1, Issue 6
  • DOI: 10.1002/wcms.66

Current status and future challenges in T-cell receptor/peptide/MHC molecular dynamics simulations
journal, February 2015

  • Knapp, B.; Demharter, S.; Esmaielbeiki, R.
  • Briefings in Bioinformatics, Vol. 16, Issue 6
  • DOI: 10.1093/bib/bbv005

The Structural Basis of Peptide-Protein Binding Strategies
journal, February 2010


Protein-Protein Interaction Investigated by Steered Molecular Dynamics: The TCR-pMHC Complex
journal, October 2008


High-resolution global peptide-protein docking using fragments-based PIPER-FlexPepDock
journal, December 2017


Protein–peptide docking: opportunities and challenges
journal, August 2018


Optimal Clustering for Detecting Near-Native Conformations in Protein Docking
journal, August 2005


The pepATTRACT web server for blind, large-scale peptide–protein docking
journal, April 2017

  • de Vries, Sjoerd J.; Rey, Julien; Schindler, Christina E. M.
  • Nucleic Acids Research, Vol. 45, Issue W1
  • DOI: 10.1093/nar/gkx335

An Efficient Metadynamics-Based Protocol To Model the Binding Affinity and the Transition State Ensemble of G-Protein-Coupled Receptor Ligands
journal, May 2017

  • Saleh, Noureldin; Ibrahim, Passainte; Saladino, Giorgio
  • Journal of Chemical Information and Modeling, Vol. 57, Issue 5
  • DOI: 10.1021/acs.jcim.6b00772

Structure and Substrate Specificity of the Pim-1 Kinase
journal, October 2005

  • Bullock, Alex N.; Debreczeni, Judit; Amos, Ann L.
  • Journal of Biological Chemistry, Vol. 280, Issue 50
  • DOI: 10.1074/jbc.M510711200

Peptides and peptide conjugates: therapeutics on the upward path
journal, August 2012

  • Ahrens, Verena M.; Bellmann-Sickert, Kathrin; Beck-Sickinger, Annette G.
  • Future Medicinal Chemistry, Vol. 4, Issue 12
  • DOI: 10.4155/fmc.12.76

Escaping free-energy minima
journal, September 2002

  • Laio, A.; Parrinello, M.
  • Proceedings of the National Academy of Sciences, Vol. 99, Issue 20
  • DOI: 10.1073/pnas.202427399

Enhanced sampling techniques in biomolecular simulations
journal, November 2015


Peptide-mediated interactions in biological systems: new discoveries and applications
journal, August 2008


Adaptive biasing force method for scalar and vector free energy calculations
journal, April 2008

  • Darve, Eric; Rodríguez-Gómez, David; Pohorille, Andrew
  • The Journal of Chemical Physics, Vol. 128, Issue 14
  • DOI: 10.1063/1.2829861

Unconstrained enhanced sampling for free energy calculations of biomolecules: a review
journal, July 2016


Calculating free energies using average force
journal, November 2001

  • Darve, Eric; Pohorille, Andrew
  • The Journal of Chemical Physics, Vol. 115, Issue 20
  • DOI: 10.1063/1.1410978

Mechanism of the G-protein mimetic nanobody binding to a muscarinic G-protein-coupled receptor
journal, March 2018

  • Miao, Yinglong; McCammon, J. Andrew
  • Proceedings of the National Academy of Sciences, Vol. 115, Issue 12
  • DOI: 10.1073/pnas.1800756115

PTRAJ and CPPTRAJ: Software for Processing and Analysis of Molecular Dynamics Trajectory Data
journal, June 2013

  • Roe, Daniel R.; Cheatham, Thomas E.
  • Journal of Chemical Theory and Computation, Vol. 9, Issue 7
  • DOI: 10.1021/ct400341p