Docking interactions determine early cleavage events in insulin proteolysis by pepsin: Experiment and simulation

Koliński, Michał; Kmiecik, Sebastian; Dec, Robert; Piejko, Marcin; Mak, Paweł; Dzwolak, Wojciech

doi:10.1016/j.ijbiomac.2020.01.253

Cited by 12 publications

(10 citation statements)

References 39 publications

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“…Its distinctive feature among other tools is the possibility of fast simulation of the large backbone rearrangements of both peptide and protein receptors during binding (see the review on protein–peptide docking tools [ 58 ]). In addition, the CABS-dock has been used in multiple applications (recently reviewed [ 56 ]), including docking to receptors with disordered fragments [ 41 , 59 ], GPCRs [ 60 ], and modeling proteolysis mechanisms [ 61 ].…”

Section: Methodsmentioning

confidence: 99%

Protein–Protein Docking with Large-Scale Backbone Flexibility Using Coarse-Grained Monte-Carlo Simulations

Kurciński

Kmiecik

Zalewski

et al. 2021

IJMS

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Most of the protein–protein docking methods treat proteins as almost rigid objects. Only the side-chains flexibility is usually taken into account. The few approaches enabling docking with a flexible backbone typically work in two steps, in which the search for protein–protein orientations and structure flexibility are simulated separately. In this work, we propose a new straightforward approach for docking sampling. It consists of a single simulation step during which a protein undergoes large-scale backbone rearrangements, rotations, and translations. Simultaneously, the other protein exhibits small backbone fluctuations. Such extensive sampling was possible using the CABS coarse-grained protein model and Replica Exchange Monte Carlo dynamics at a reasonable computational cost. In our proof-of-concept simulations of 62 protein–protein complexes, we obtained acceptable quality models for a significant number of cases.

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Section: Methodsmentioning

confidence: 99%

Protein–Protein Docking with Large-Scale Backbone Flexibility Using Coarse-Grained Monte-Carlo Simulations

Kurciński

Kmiecik

Zalewski

et al. 2021

IJMS

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“…In recent years, CABS-dock has been applied or extended to different modeling tasks. These include peptide docking with large structural changes of the receptor structure and disordered structures [ 7 , 8 ], docking with protein–peptide contact information [ 20 ], docking of peptides to GPCR structures [ 24 ] (see also recent review on CABS-dock development and applications [ 6 ]), and identification of peptide cleavage sites for protease–substrate systems [ 9 ].…”

Section: Methodsmentioning

confidence: 99%

“…Appropriate coarse-graining of the protein/peptide structure and a very efficient Monte Carlo sampling of the system dynamics enable an exhaustive search of the conformational space and unrestrained docking of even quite long peptides (or small proteins). Several peptides can be docked simultaneously [ 9 ]. Of course, coarse-graining of conformational space and inevitable smoothening of energy surface (CABS uses knowledge-based statistical potentials—see the Materials and Methods section and References for more details) leads to imprecise energy scaling of the docked structures.…”

Section: Introductionmentioning

confidence: 99%

Molecular Dynamics Scoring of Protein–Peptide Models Derived from Coarse-Grained Docking

2021

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One of the major challenges in the computational prediction of protein–peptide complexes is the scoring of predicted models. Usually, it is very difficult to find the most accurate solutions out of the vast number of sometimes very different and potentially plausible predictions. In this work, we tested the protocol for Molecular Dynamics (MD)-based scoring of protein–peptide complex models obtained from coarse-grained (CG) docking simulations. In the first step of the scoring procedure, all models generated by CABS-dock were reconstructed starting from their original C-alpha trace representations to all-atom (AA) structures. The second step included geometry optimization of the reconstructed complexes followed by model scoring based on receptor–ligand interaction energy estimated from short MD simulations in explicit water. We used two well-known AA MD force fields, CHARMM and AMBER, and a CG MARTINI force field. Scoring results for 66 different protein–peptide complexes show that the proposed MD-based scoring approach can be used to identify protein–peptide models of high accuracy. The results also indicate that the scoring accuracy may be significantly affected by the quality of the reconstructed protein receptor structures.

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“…CABS-dock uses a very efficient simulation approach, the CABS coarse-grained protein model (its broad applications in protein modeling, protein structure prediction, simulation of protein flexibility and disordered states have been recently summarized in the reviews [ 33–35 ]. CABS-dock has been first introduced as a web server [ 36–38 ] and successfully applied to modeling large-scale conformation changes of protein receptor during peptide binding [ 39 ], protein–protein docking [ 38 ], peptide docking using sparse information on protein–peptide residue-residue contacts [ 40 ] and modeling the cleavage events occurring during proteolytic peptide degradation [ 41 ]. Recently, CABS-dock has been made available as a standalone application [ 20 ], which contains many features and extensions for advanced users.…”

Section: Methodsmentioning

confidence: 99%

Docking of peptides to GPCRs using a combination of CABS-dock with FlexPepDock refinement

Badaczewska-Dawid¹,

Kmiecik²,

Koliński³

2020

Briefings in Bioinformatics

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The structural description of peptide ligands bound to G protein-coupled receptors (GPCRs) is important for the discovery of new drugs and deeper understanding of the molecular mechanisms of life. Here we describe a three-stage protocol for the molecular docking of peptides to GPCRs using a set of different programs: (1) CABS-dock for docking fully flexible peptides; (2) PD2 method for the reconstruction of atomistic structures from C-alpha traces provided by CABS-dock and (3) Rosetta FlexPepDock for the refinement of protein–peptide complex structures and model scoring. We evaluated the proposed protocol on the set of seven different GPCR–peptide complexes (including one containing a cyclic peptide), for which crystallographic structures are available. We show that CABS-dock produces high resolution models in the sets of top-scored models. These sets of models, after reconstruction to all-atom representation, can be further improved by Rosetta high-resolution refinement and/or minimization, leading in most of the cases to sub-Angstrom accuracy in terms of interface root-mean-square-deviation measure.

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Docking interactions determine early cleavage events in insulin proteolysis by pepsin: Experiment and simulation

Cited by 12 publications

References 39 publications

Protein–Protein Docking with Large-Scale Backbone Flexibility Using Coarse-Grained Monte-Carlo Simulations

Protein–Protein Docking with Large-Scale Backbone Flexibility Using Coarse-Grained Monte-Carlo Simulations

Molecular Dynamics Scoring of Protein–Peptide Models Derived from Coarse-Grained Docking

Docking of peptides to GPCRs using a combination of CABS-dock with FlexPepDock refinement

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