Activation and friction in enzymatic loop opening and closing dynamics
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Otros documentos de la autoría: Zinovjev, Kirill; Guénon, Paul; Ramos Guzmán, Carlos Alberto; Ruiz-Pernía, José Javier; Laage, Damien; Tuñón, Iñaki
Metadatos
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comunitat-uji-handle2:10234/160292
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INVESTIGACIONMetadatos
Título
Activation and friction in enzymatic loop opening and closing dynamicsAutoría
Fecha de publicación
2024-03-20Editor
Springer NatureISSN
2041-1723Cita bibliográfica
Zinovjev, K., Guénon, P., Ramos-Guzmán, C.A. et al. (2024). Activation and friction in enzymatic loop opening and closing dynamics. Nature Communications 15, 2490.Tipo de documento
info:eu-repo/semantics/articleVersión
info:eu-repo/semantics/publishedVersionPalabras clave / Materias
Resumen
Protein loop dynamics have recently been recognized as central to enzymatic activity, specificity and stability. However, the factors controlling loop opening and closing kinetics have remained elusive. Here, we combine ... [+]
Protein loop dynamics have recently been recognized as central to enzymatic activity, specificity and stability. However, the factors controlling loop opening and closing kinetics have remained elusive. Here, we combine molecular dynamics simulations with string-method determination of complex reaction coordinates to elucidate the molecular mechanism and rate-limiting step for WPD-loop dynamics in the PTP1B enzyme. While protein conformational dynamics is often represented as diffusive motion hindered by solvent viscosity and internal friction, we demonstrate that loop opening and closing is activated. It is governed by torsional rearrangement around a single loop peptide group and by significant friction caused by backbone adjustments, which can dynamically trap the loop. Considering both torsional barrier and time-dependent friction, our calculated rate constants exhibit very good agreement with experimental measurements, reproducing the change in loop opening kinetics between proteins. Furthermore, we demonstrate the applicability of our results to other enzymatic loops, including the M20 DHFR loop, thereby offering prospects for loop engineering potentially leading to enhanced designs. [-]
Publicado en
Nature Communications, Vol. 15 (2024)Entidad financiadora
Ministerio de Ciencia e Innovación / Agencia Estatal de Investigación | Generalitat Valenciana
Código del proyecto o subvención
PID2021-123332OB-C22 | PROMETEO CIPROM/2021/079
Derechos de acceso
info:eu-repo/semantics/openAccess
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