Parallel Temperature Replica-Exchange Molecular Dynamics Simulations Capture the Observed Impact of Stapling on Coiled-Coil Conformational Stability
Macrocyclization or stapling is an important strategy for increasing the conformational stability and target-binding affinity of peptides and proteins, especially in therapeutic contexts. Atomistic simulations of such stapled peptides and proteins could help rationalize existing experimental data an...
Saved in:
| Main Author: | |
|---|---|
| Published: |
2025
|
| Subjects: | |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1852023746793046016 |
|---|---|
| author | Joshua L. Price (1703641) |
| author_facet | Joshua L. Price (1703641) |
| author_role | author |
| dc.creator.none.fl_str_mv | Joshua L. Price (1703641) |
| dc.date.none.fl_str_mv | 2025-01-09T21:45:30Z |
| dc.identifier.none.fl_str_mv | 10.1021/acs.jpcb.4c06974.s024 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/media/Parallel_Temperature_Replica-Exchange_Molecular_Dynamics_Simulations_Capture_the_Observed_Impact_of_Stapling_on_Coiled-Coil_Conformational_Stability/28179647 |
| dc.rights.none.fl_str_mv | CC BY-NC 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biophysics Biochemistry Biotechnology Computational Biology Biological Sciences not elsewhere classified Chemical Sciences not elsewhere classified Physical Sciences not elsewhere classified Information Systems not elsewhere classified values closely match standard approaches exist provide predictive tools parallel temperature replica force fields required resulting simulations would peptide conformational stability force field parameters several stapled coiled new stapled peptides </ sub >) conformational stability stapled peptides >< sub </ sub variant relative variant along trends among sufficiently realistic previous experiments physically realistic nonstapled counterparts nonstapled counterpart md simulations intensive nature important strategy g </ functional groups coil variants binding affinity atomistic simulations |
| dc.title.none.fl_str_mv | Parallel Temperature Replica-Exchange Molecular Dynamics Simulations Capture the Observed Impact of Stapling on Coiled-Coil Conformational Stability |
| dc.type.none.fl_str_mv | Dataset Media info:eu-repo/semantics/publishedVersion dataset |
| description | Macrocyclization or stapling is an important strategy for increasing the conformational stability and target-binding affinity of peptides and proteins, especially in therapeutic contexts. Atomistic simulations of such stapled peptides and proteins could help rationalize existing experimental data and provide predictive tools for the design of new stapled peptides and proteins. Standard approaches exist for incorporating nonstandard amino acids and functional groups into the force fields required for MD simulations and have been used in the context of stapling for more than a decade. However, enthusiasm for their use has been limited by their time-intensive nature and concerns about whether the resulting simulations would be physically realistic. Here, we report the development of force field parameters for two unnatural triazole staples, which we have incorporated into implicit-solvent parallel temperature replica-exchange molecular dynamics simulations of several stapled coiled-coil variants and their nonstapled counterparts. We used these simulations to calculate melting temperatures (<i>T</i><sub>m</sub>) of each variant along with the impact of stapling on the conformational stability of each variant relative to its nonstapled counterpart (ΔΔ<i>G</i>). Trends among these simulated <i>T</i><sub>m</sub> and ΔΔ<i>G</i> values closely match those observed in previous experiments, suggesting that the parameters we developed for these staples are sufficiently realistic to be useful in predicting the impact of stapling on the protein/peptide conformational stability in other contexts. |
| eu_rights_str_mv | openAccess |
| id | Manara_a0836394d8d38bd6a9ddc19aa918e708 |
| identifier_str_mv | 10.1021/acs.jpcb.4c06974.s024 |
| network_acronym_str | Manara |
| network_name_str | ManaraRepo |
| oai_identifier_str | oai:figshare.com:article/28179647 |
| publishDate | 2025 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY-NC 4.0 |
| spelling | Parallel Temperature Replica-Exchange Molecular Dynamics Simulations Capture the Observed Impact of Stapling on Coiled-Coil Conformational StabilityJoshua L. Price (1703641)BiophysicsBiochemistryBiotechnologyComputational BiologyBiological Sciences not elsewhere classifiedChemical Sciences not elsewhere classifiedPhysical Sciences not elsewhere classifiedInformation Systems not elsewhere classifiedvalues closely matchstandard approaches existprovide predictive toolsparallel temperature replicaforce fields requiredresulting simulations wouldpeptide conformational stabilityforce field parametersseveral stapled coilednew stapled peptides</ sub >)conformational stabilitystapled peptides>< sub</ subvariant relativevariant alongtrends amongsufficiently realisticprevious experimentsphysically realisticnonstapled counterpartsnonstapled counterpartmd simulationsintensive natureimportant strategyg </functional groupscoil variantsbinding affinityatomistic simulationsMacrocyclization or stapling is an important strategy for increasing the conformational stability and target-binding affinity of peptides and proteins, especially in therapeutic contexts. Atomistic simulations of such stapled peptides and proteins could help rationalize existing experimental data and provide predictive tools for the design of new stapled peptides and proteins. Standard approaches exist for incorporating nonstandard amino acids and functional groups into the force fields required for MD simulations and have been used in the context of stapling for more than a decade. However, enthusiasm for their use has been limited by their time-intensive nature and concerns about whether the resulting simulations would be physically realistic. Here, we report the development of force field parameters for two unnatural triazole staples, which we have incorporated into implicit-solvent parallel temperature replica-exchange molecular dynamics simulations of several stapled coiled-coil variants and their nonstapled counterparts. We used these simulations to calculate melting temperatures (<i>T</i><sub>m</sub>) of each variant along with the impact of stapling on the conformational stability of each variant relative to its nonstapled counterpart (ΔΔ<i>G</i>). Trends among these simulated <i>T</i><sub>m</sub> and ΔΔ<i>G</i> values closely match those observed in previous experiments, suggesting that the parameters we developed for these staples are sufficiently realistic to be useful in predicting the impact of stapling on the protein/peptide conformational stability in other contexts.2025-01-09T21:45:30ZDatasetMediainfo:eu-repo/semantics/publishedVersiondataset10.1021/acs.jpcb.4c06974.s024https://figshare.com/articles/media/Parallel_Temperature_Replica-Exchange_Molecular_Dynamics_Simulations_Capture_the_Observed_Impact_of_Stapling_on_Coiled-Coil_Conformational_Stability/28179647CC BY-NC 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/281796472025-01-09T21:45:30Z |
| spellingShingle | Parallel Temperature Replica-Exchange Molecular Dynamics Simulations Capture the Observed Impact of Stapling on Coiled-Coil Conformational Stability Joshua L. Price (1703641) Biophysics Biochemistry Biotechnology Computational Biology Biological Sciences not elsewhere classified Chemical Sciences not elsewhere classified Physical Sciences not elsewhere classified Information Systems not elsewhere classified values closely match standard approaches exist provide predictive tools parallel temperature replica force fields required resulting simulations would peptide conformational stability force field parameters several stapled coiled new stapled peptides </ sub >) conformational stability stapled peptides >< sub </ sub variant relative variant along trends among sufficiently realistic previous experiments physically realistic nonstapled counterparts nonstapled counterpart md simulations intensive nature important strategy g </ functional groups coil variants binding affinity atomistic simulations |
| status_str | publishedVersion |
| title | Parallel Temperature Replica-Exchange Molecular Dynamics Simulations Capture the Observed Impact of Stapling on Coiled-Coil Conformational Stability |
| title_full | Parallel Temperature Replica-Exchange Molecular Dynamics Simulations Capture the Observed Impact of Stapling on Coiled-Coil Conformational Stability |
| title_fullStr | Parallel Temperature Replica-Exchange Molecular Dynamics Simulations Capture the Observed Impact of Stapling on Coiled-Coil Conformational Stability |
| title_full_unstemmed | Parallel Temperature Replica-Exchange Molecular Dynamics Simulations Capture the Observed Impact of Stapling on Coiled-Coil Conformational Stability |
| title_short | Parallel Temperature Replica-Exchange Molecular Dynamics Simulations Capture the Observed Impact of Stapling on Coiled-Coil Conformational Stability |
| title_sort | Parallel Temperature Replica-Exchange Molecular Dynamics Simulations Capture the Observed Impact of Stapling on Coiled-Coil Conformational Stability |
| topic | Biophysics Biochemistry Biotechnology Computational Biology Biological Sciences not elsewhere classified Chemical Sciences not elsewhere classified Physical Sciences not elsewhere classified Information Systems not elsewhere classified values closely match standard approaches exist provide predictive tools parallel temperature replica force fields required resulting simulations would peptide conformational stability force field parameters several stapled coiled new stapled peptides </ sub >) conformational stability stapled peptides >< sub </ sub variant relative variant along trends among sufficiently realistic previous experiments physically realistic nonstapled counterparts nonstapled counterpart md simulations intensive nature important strategy g </ functional groups coil variants binding affinity atomistic simulations |