The computational study of conformational transitions in nucleic acids still faces many challenges. For example, in the case of single stranded RNA tetranucleotides, agreement between simulations and experiments is not satisfactory due to inaccuracies in the force fields commonly used in molecular dynamics. Improvement of force fields is however hindered by the diiculties of decoupling those errors from the statistical errors caused by insuicient sampling. We here tackle both problems by introducing a novel enhancing sampling method and using experimental data to improve RNA force fields. In this novel method, concurrent well-tempered metadynamics are integrated in a Hamiltonian replica-exchange scheme. The ladder of replicas is built with different strength of the bias potential exploiting the tunability of well-tempered metadynamics. Using this method, free-energy barriers associated to individual collective variables are significantly reduced compared with simple force-field scaling. The introduced methodology is flexible and allows adaptive bias potentials to be self-consistently constructed for a large number of simple collective variables, such as distances and dihedral angles. Additionally, a modified metadynamics algorithm is used to calculate correcting potentials designed to enforce distributions of backbone torsion angles taken from experimental structures. Replica-exchange simulations of tetranucleotides including these correcting potentials show significantly better agreement with independent solution experiments for the oligonucleotides containing pyrimidine bases. Although the proposed corrections do not seem to be portable to generic RNA systems, the simulations reveal the importance of the α and ζ backbone angles for the modulation of the RNA conformational ensemble. The correction protocol presented here suggests a systematic procedure for force-field refinement.

Enhanced sampling and force field corrections for RNA oligomers / Gil Ley, Alejandro. - (2016 Oct 20).

Enhanced sampling and force field corrections for RNA oligomers

Gil Ley, Alejandro
2016-10-20

Abstract

The computational study of conformational transitions in nucleic acids still faces many challenges. For example, in the case of single stranded RNA tetranucleotides, agreement between simulations and experiments is not satisfactory due to inaccuracies in the force fields commonly used in molecular dynamics. Improvement of force fields is however hindered by the diiculties of decoupling those errors from the statistical errors caused by insuicient sampling. We here tackle both problems by introducing a novel enhancing sampling method and using experimental data to improve RNA force fields. In this novel method, concurrent well-tempered metadynamics are integrated in a Hamiltonian replica-exchange scheme. The ladder of replicas is built with different strength of the bias potential exploiting the tunability of well-tempered metadynamics. Using this method, free-energy barriers associated to individual collective variables are significantly reduced compared with simple force-field scaling. The introduced methodology is flexible and allows adaptive bias potentials to be self-consistently constructed for a large number of simple collective variables, such as distances and dihedral angles. Additionally, a modified metadynamics algorithm is used to calculate correcting potentials designed to enforce distributions of backbone torsion angles taken from experimental structures. Replica-exchange simulations of tetranucleotides including these correcting potentials show significantly better agreement with independent solution experiments for the oligonucleotides containing pyrimidine bases. Although the proposed corrections do not seem to be portable to generic RNA systems, the simulations reveal the importance of the α and ζ backbone angles for the modulation of the RNA conformational ensemble. The correction protocol presented here suggests a systematic procedure for force-field refinement.
20-ott-2016
Gil-Ley, Alejandro
Bussi, Giovanni
Gil Ley, Alejandro
File in questo prodotto:
File Dimensione Formato  
1963_35248_AGL_SISSA_PhD_thesis.pdf

accesso aperto

Tipologia: Tesi
Licenza: Non specificato
Dimensione 16.75 MB
Formato Adobe PDF
16.75 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.11767/4628
 Attenzione

Attenzione! I dati visualizzati non sono stati sottoposti a validazione da parte dell'ateneo

Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus ND
  • ???jsp.display-item.citation.isi??? ND
social impact