The oxDNA model of Deoxyribonucleic acid has been applied widely to systems in biology, biophysics and nanotechnology. It is currently available via two independent open source packages. Here we present a set of clearly documented exemplar simulations that simultaneously provide both an introduction to simulating the model, and a review of the model’s fundamental properties. We outline how simulation results can be interpreted in terms of—and feed into our understanding of—less detailed models that operate at larger length scales, and provide guidance on whether simulating a system with oxDNA is worthwhile.
The ever increasing computer power, together with the improved accuracy of atomistic force fields, enables researchers to investigate biological systems at the molecular level with remarkable detail. However, the relevant length and time scales of many processes of interest are still hardly within reach even for state-of-the-art hardware, thus leaving important questions often unanswered. The computer-aided investigation of many biological physics problems thus largely benefits from the usage of coarse-grained models, that is, simplified representations of a molecule at a level of resolution that is lower than atomistic. A plethora of coarse-grained models have been developed, which differ most notably in their granularity; this latter aspect determines one of the crucial open issues in the field, i.e. the identification of an optimal degree of coarsening, which enables the greatest simplification at the expenses of the smallest information loss. In this review, we present the problem of coarse-grained modeling in biophysics from the viewpoint of system representation and information content. In particular, we discuss two distinct yet complementary aspects of protein modeling: on the one hand, the relationship between the resolution of a model and its capacity of accurately reproducing the properties of interest; on the other hand, the possibility of employing a lower resolution description of a detailed model to extract simple, useful, and intelligible information from the latter.
Cryogenic electron tomography (cryo-ET) allows structural determination of biomolecules in their native environment (in situ). Its potential of providing information on the dynamics of macromolecular complexes in cells is still largely unexploited, due to the challenges of the data analysis. The crowded cell environment and continuous conformational changes of complexes make difficult disentangling the data heterogeneity. We present HEMNMA-3D, which is, to the best of our knowledge, the first method for analyzing cryo electron subtomograms in terms of continuous conformational changes of complexes. HEMNMA-3D uses a combination of elastic and rigid-body 3D-to-3D iterative alignments of a flexible 3D reference (atomic structure or electron microscopy density map) to match the conformation, orientation, and position of the complex in each subtomogram. The elastic matching combines molecular mechanics simulation (Normal Mode Analysis of the 3D reference) and experimental, subtomogram data analysis. The rigid-body alignment includes compensation for the missing wedge, due to the limited tilt angle of cryo-ET. The conformational parameters (amplitudes of normal modes) of the complexes in subtomograms obtained through the alignment are processed to visualize the distribution of conformations in a space of lower dimension (typically, 2D or 3D) referred to as space of conformations. This allows a visually interpretable insight into the dynamics of the complexes, by calculating 3D averages of subtomograms with similar conformations from selected (densest) regions and by recording movies of the 3D reference's displacement along selected trajectories through the densest regions. We describe HEMNMA-3D and show its validation using synthetic datasets. We apply HEMNMA-3D to an experimental dataset describing in situ nucleosome conformational variability. HEMNMA-3D software is available freely (open-source) as part of ContinuousFlex plugin of Scipion V3.0 (http://scipion.i2pc.es).
Recent advances in methodology enable effective coarse-grained modeling of deoxyribonucleic acid (DNA) based on underlying atomistic force field simulations. The so-called bottom-up coarse-graining practice separates fast and slow dynamic processes in molecular systems by averaging out fast degrees of freedom represented by the underlying fine-grained model. The resulting effective potential of interaction includes the contribution from fast degrees of freedom effectively in the form of potential of mean force. The pair-wise additive potential is usually adopted to construct the coarse-grained Hamiltonian for its efficiency in a computer simulation. In this review, we present a few well-developed bottom-up coarse-graining methods, discussing their application in modeling DNA properties such as DNA flexibility (persistence length), conformation, “melting,” and DNA condensation.
Frontiers in Molecular Biosciences
Function and Dysfunction of Large Bio-Molecules Assemblies: Insights from Multidisciplinary Computational Approaches