Consistent View of Protein Fluctuations from All-Atom Molecular Dynamics and Coarse-Grained Dynamics with Knowledge-Based Force-Field

Abstract

It is widely recognized that atomistic Molecular Dynamics (MD), a classical simulation method, captures the essential physics of protein dynamics. That idea is supported by a theoretical study showing that various MD force-fields provide a consensus picture of protein fluctuations in aqueous solution [Rueda, M. et al. Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 796-801]. However, atomistic MD cannot be applied to most biologically relevant processes due to its limitation to relatively short time scales. Much longer time scales can be accessed by properly designed coarse-grained models. We demonstrate that the aforementioned consensus view of protein dynamics from short (nanosecond) time scale MD simulations is fairly consistent with the dynamics of the coarse-grained protein model - the CABS model. The CABS model employs stochastic dynamics (a Monte Carlo method) and a knowledge-based force-field, which is not biased toward the native structure of a simulated protein. Since CABS-based dynamics allows for the simulation of entire folding (or multiple folding events) in a single run, integration of the CABS approach with all-atom MD promises a convenient (and computationally feasible) means for the long-time multiscale molecular modeling of protein systems with atomistic resolution.

Coarse-Grained Protein Models and Their Applications

“…Very efficient models based on three/four united atoms per amino acid residue accelerate simulations by 3−4 orders of magnitude in comparison with classical all-atom MD simulations. 211,271 Nevertheless, it is useful to develop even more simplified models dedicated to large protein systems with r e a l i s t i c c o n n e c t i o n w i t h a l l -a t o m r e s o l u t i o n schemes. 28,225,314,407 On the other hand, some applications require a fine level of coarse-graining.…”

CABS-flex: server for fast simulation of protein structure fluctuations

“…CABS, the well-established coarse-grained protein modeling tool, may generate consistent protein dynamics at highly reduced (three orders of magnitude) cost (2–6), although with some decrease of the resolution. The CABS-flex server follows the work of Jamroz et al (2), where the authors demonstrated that the consensus view of protein near-native dynamics obtained from 10-ns MD simulations (all-atom, explicit water, for all protein metafolds using the four most popular force fields) is consistent with the CABS dynamics. The CABS-flex pipeline uses the CABS simulation protocol for near-native dynamics of globular proteins [for the development and optimization details see (2)].…”

“…The CABS-flex server follows the work of Jamroz et al (2), where the authors demonstrated that the consensus view of protein near-native dynamics obtained from 10-ns MD simulations (all-atom, explicit water, for all protein metafolds using the four most popular force fields) is consistent with the CABS dynamics. The CABS-flex pipeline uses the CABS simulation protocol for near-native dynamics of globular proteins [for the development and optimization details see (2)]. The resulting trajectory is analyzed and clustered (and thus reduced) to a representative ensemble of protein models reflecting the flexibility of the input structure.…”

CABS-flex predictions of protein flexibility compared with NMR ensembles

“…The CABS-flex simulation length has been optimized to obtain the best possible convergence with the 10 ns MD simulations [see details in Jamroz et al (2013b)]. …”