Exploring Conformational Landscapes Along Anharmonic Low-Frequency Vibrations
arxiv(2024)
摘要
We aim to automatize the identification of collective variables to simplify
and speed up enhanced sampling simulations of conformational dynamics in
biomolecules. We focus on anharmonic low-frequency vibrations that exhibit
fluctuations on timescales faster than conformational transitions but describe
a path of least resistance towards structural change. A key challenge is that
harmonic approximations are ill-suited to characterize these vibrations, which
are observed at far-infrared frequencies and are easily excited by thermal
collisions at room temperature.
Here, we approached this problem with a frequency-selective anharmonic
(FRESEAN) mode analysis that does not rely on harmonic approximations and
successfully isolates anharmonic low-frequency vibrations from short molecular
dynamics simulation trajectories. We applied FRESEAN mode analysis to
simulations of alanine dipeptide, a common test system for enhanced sampling
simulation protocols, and compare the performance of isolated low-frequency
vibrations to conventional user-defined collective variables (here backbone
dihedral angles) in enhanced sampling simulations.
The comparison shows that enhanced sampling along anharmonic low-frequency
vibrations not only reproduces known conformational dynamics but can even
further improve sampling of slow transitions compared to user-defined
collective variables. Notably, free energy surfaces spanned by low-frequency
anharmonic vibrational modes exhibit lower barriers associated with
conformational transitions relative to representations in backbone dihedral
space. We thus conclude that anharmonic low-frequency vibrations provide a
promising path for highly effective and fully automated enhanced sampling
simulations of conformational dynamics in biomolecules.
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