J 2015

Insights into Stability and Folding of GNRA and UNCG Tetra loops Revealed by Microsecond Molecular Dynamics and Well-Tempered Metadynamics

HALDAR, Susanta, Petra KUHROVÁ, Pavel BANÁŠ, Vojtěch SPIWOK, Jiří ŠPONER et. al.

Basic information

Original name

Insights into Stability and Folding of GNRA and UNCG Tetra loops Revealed by Microsecond Molecular Dynamics and Well-Tempered Metadynamics

Authors

HALDAR, Susanta, Petra KUHROVÁ, Pavel BANÁŠ, Vojtěch SPIWOK, Jiří ŠPONER, Pavel HOBZA and Michal OTYEPKA

Edition

Journal of Chemical Theory and Computation, WASHINGTON, AMER CHEMICAL SOC, 2015, 1549-9618

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

10403 Physical chemistry

Country of publisher

United States of America

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

Impact factor

Impact factor: 5.301

Organization unit

Central European Institute of Technology

DOI

UT WoS

000359500000034

Keywords in English

FREE-ENERGY LANDSCAPE; DI-GMP RIBOSWITCH; RNA HAIRPINS; DISTINCTIVE FEATURES; ANGSTROM RESOLUTION; HAMMERHEAD RIBOZYME; BACTERIAL RIBOSOME; REPLICA-EXCHANGE; SIMULATIONS; KINETICS

Tags

Tags

International impact, Reviewed
Změněno: 30/3/2016 16:56, Mgr. Eva Špillingová

Abstract

V originále

RNA hairpins capped by 5'-GNRA-3' or 5'-UNCG-3' tetraloops (TLs) are prominent RNA structural motifs. Despite their small size, a wealth of experimental data, and recent progress in theoretical simulations of their structural dynamics and folding, our understanding of the folding and unfolding processes of these small RNA elements is still limited. Theoretical description of the folding and unfolding processes requires robust sampling, which can be achieved by either an exhaustive time scale in standard molecular dynamics simulations or sophisticated enhanced sampling methods, using temperature acceleration or biasing potentials. Here, we study structural dynamics of 5'-GNRA-3' and 5'-UNCG-3' TLs by 15,us-long standard simulations and a series of well-tempered metadynamics, attempting to accelerate sampling by bias in a few chosen collective variables (CVs). Both methods provide useful insights. The unfolding and refolding mechanisms of the GNRA TL observed by well-tempered metadynamics agree with the (reverse) folding mechanism suggested by recent replica exchange molecular dynamics simulations. The orientation of the glycosidic bond of the G(L4) nudeobase is critical for the UUCG TL folding pathway, and our data strongly support the hypothesis that G(L4)-anti forms a kinetic trap along the folding pathway. Along with giving useful insight, our study also demonstrates that using only a few CVs apparently does not capture the full folding landscape of the RNA TLs. Despite using several sophisticated selections of the CVs, formation of the loop appears to remain a hidden variable, preventing a full convergence of the metadynamics. Finally, our data suggest that the unfolded state might be overstabilized by the force fields used.