Standard Binding Free Energy of a SIM–SUMO Complex

Kötter, Alex; Mootz, Henning D.; Heuer, Andreas

doi:10.1021/acs.jctc.9b00428

Cited by 10 publications

(7 citation statements)

References 51 publications

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“…Large-scale studies on pharmaceutically relevant ligandreceptor pairs indicate that free energy estimates from MD simulation exhibit systematic errors in the range of 1 kcal/ mol (36). The statistical error found for affinity estimates with the method used in this study is typically much lower, even when shorter simulation times were used (18,37). This suggests that statistical errors can indicate higher accuracy than we actually have.…”

Section: Estimation Of Affinitiesmentioning

confidence: 58%

“…We used atomistic molecular dynamics (MD) simulations to investigate structural properties of complexes formed by peptides containing SIM2 or SIM3 of RNF4 and SUMO3 (see Table 1). We used the method of Woo and Roux (17) to estimate the affinities of the SIM2 and SIM3 peptides to SUMO, which also directly allowed us to quantify the contribution of either binding orientation to the overall affinity (18).…”

Section: Introductionmentioning

confidence: 99%

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Insights into the Microscopic Structure of RNF4-SIM-SUMO Complexes from MD Simulations

Kötter

Mootz

Heuer

2020

Biophysical Journal

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Post-translational modification with one of the isoforms of the small ubiquitin-like modifier (SUMO) affects thousands of proteins in the human proteome. The binding of SUMO to SUMO interacting motifs (SIMs) can translate the SUMOylation event into functional consequences. The E3 ubiquitin ligase RNF4 contains multiple SIMs and connects SUMOylation to the ubiquitin pathway. SIM2 and SIM3 of RNF4 were shown to be the most important motifs to recognize SUMO chains. However, the study of SIM-SUMO complexes is complicated by their typically low affinity and variable binding of the SIMs in parallel and antiparallel orientations. We investigated properties of complexes formed by SUMO3 with peptides containing either SIM2 or SIM3 using molecular dynamics simulations. The affinities of the complexes were determined using a state-of-the-art free energy protocol and were found to be in good agreement with experimental data, thus corroborating our method. Long unrestrained simulations allowed a new interpretation of experimental results regarding the structure of the SIM-SUMO interface. We show that both SIM2 and SIM3 bind SUMO3 in parallel and antiparallel orientations and identified main interaction sites for acidic residues flanking the SIM. We noticed unusual SIM-SUMO interfaces in a previously reported NMR structure (PDB: 2mp2) of a complex formed by a SUMO3 dimer with the bivalent SIM2-SIM3 peptide. Computational determination of the individual SIM-SUMO affinities based on these structural arrangements yielded significantly higher dissociation constants. To our knowledge, our approach adds new opportunities to characterize individual SIM-SUMO complexes and suggests that further studies will be necessary to understand these interactions when occurring in multivalent form.

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Section: Estimation Of Affinitiesmentioning

confidence: 58%

Section: Introductionmentioning

confidence: 99%

Insights into the Microscopic Structure of RNF4-SIM-SUMO Complexes from MD Simulations

Kötter

Mootz

Heuer

2020

Biophysical Journal

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“…It has been suggested [ 13 ] that the parallel binding by the PIASX SIM is preferred because the parallel orientation optimizes non-polar contacts between the hhxh SIM core and SUMO. This conclusion is challenged, however, by a molecular dynamics simulation of binding between the SIM in PIAS1 (a close relative of PIASX) and SUMO-3 [ 21 ]. This simulation suggests that the core binds with similar affinity to the SUMO hydrophobic groove in either the parallel or the antiparallel orientation.…”

Section: Sim Structure and Regulation Of Sim/sumo Complex Formationmentioning

confidence: 99%

SUMO Interacting Motifs: Structure and Function

Yau

Sander

Eidson

et al. 2021

Cells

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Small ubiquitin-related modifier (SUMO) is a member of the ubiquitin-related protein family. SUMO modulates protein function through covalent conjugation to lysine residues in a large number of proteins. Once covalently conjugated to a protein, SUMO often regulates that protein’s function by recruiting other cellular proteins. Recruitment frequently involves a non-covalent interaction between SUMO and a SUMO-interacting motif (SIM) in the interacting protein. SIMs generally consist of a four-residue-long hydrophobic stretch of amino acids with aliphatic non-polar side chains flanked on one side by negatively charged amino acid residues. The SIM assumes an extended β-strand-like conformation and binds to a conserved hydrophobic groove in SUMO. In addition to hydrophobic interactions between the SIM non-polar core and hydrophobic residues in the groove, the negatively charged residues in the SIM make favorable electrostatic contacts with positively charged residues in and around the groove. The SIM/SUMO interaction can be regulated by the phosphorylation of residues adjacent to the SIM hydrophobic core, which provide additional negative charges for favorable electrostatic interaction with SUMO. The SUMO interactome consists of hundreds or perhaps thousands of SIM-containing proteins, but we do not fully understand how each SUMOylated protein selects the set of SIM-containing proteins appropriate to its function. SIM/SUMO interactions have critical functions in a large number of essential cellular processes including the formation of membraneless organelles by liquid–liquid phase separation, epigenetic regulation of transcription through histone modification, DNA repair, and a variety of host–pathogen interactions.

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“…It has been shown that the geometrical approach accurately predicts protein−ligand binding energies. 44,45 We used the default set up of the binding free energy estimator as described by Chipot and coworkers. 46 More details on theoretical background of the geometrical (i.e., potential-of-mean-force) free energy calculations can be obtained elsewhere.…”

Section: Binding Energy Calculationsmentioning

confidence: 99%

Computational Design of Potent Inhibitors for SARS-CoV-2’s Main Protease

A¹,

Abu-Saleh²,

Ibrahim

et al. 2020

Preprint

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In silico drug design can play a vital role in identifying promising drug candidates against COVID-19. Herein, we focused on the main protease of SARS-CoV-2 that plays crucial biological functions in the virus. We performed a ligand-based virtual screening followed by a docking screening for testing approved drugs and bioactive compounds listed in the DrugBank and ChEMBL databases. The top 8 docking results were advanced to all-atom MD simulations to study the relative stability of the protein-ligand interactions.Our results suggest several promising approved and bioactive inhibitors of SARS-CoV-2 Mpro.

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Standard Binding Free Energy of a SIM–SUMO Complex

Cited by 10 publications

References 51 publications

Insights into the Microscopic Structure of RNF4-SIM-SUMO Complexes from MD Simulations

Insights into the Microscopic Structure of RNF4-SIM-SUMO Complexes from MD Simulations

SUMO Interacting Motifs: Structure and Function

Computational Design of Potent Inhibitors for SARS-CoV-2’s Main Protease

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