Innovative interactive flexible docking method for multi-scale reconstruction elucidates dystrophin molecular assembly

Abstract

At present, our molecular knowledge of dystrophin, the protein encoded by the DMD gene and mutated in myopathy patients, remains limited. To get around the absence of its atomic structure, we have developed an innovative interactive docking method based on the BioSpring software in combination with Small-angle X-ray Scattering (SAXS) data. BioSpring allows interactive handling of biological macromolecules thanks to an augmented Elastic Network Model (aENM) that combines the spring network with non-bonded terms between atoms or pseudo-atoms. This approach can be used for building molecular assemblies even on a desktop or a laptop computer thanks to code optimizations including parallel computing and GPU programming. By combining atomistic and coarse-grained models, the approach significantly simplifies the set-up of multi-scale scenarios. BioSpring is remarkably efficient for the preparation of numeric simulations or for the design of biomolecular models integrating qualitative experimental data restraints. The combination of this program and SAXS allowed us to propose the first high-resolution models of the filamentous central domain of dystrophin, covering repeats 11 to 17. Low-resolution interactive docking experiments driven by a potential grid enabled us to propose how dystrophin may associate with F-actin and nNOS. This information provides an insight into medically relevant discoveries to come.

Dystrophin's central domain forms a complex filament that becomes disorganized by in-frame deletions

“…Dystrophin fragments homology models (with spectrin as structural pattern) were adjusted to the molecular shape by multiple interactive simulations exploring headto-tail initial positions of the protein fragment (see Supplemental Movie and Supporting Information for details). All the final models were refined by a standard energy-minimization (27). Evaluation of the final structural models was performed using standard quality controls (Table S3, data provided by http://services.mbi.ucla.edu/SAVES).…”

“…This allowed to identify general structural features over the models of a given fragment, and thus, the result of the GASBOR computation with the smallest χ 2 was finally conserved as the unique ab initio model of each dystrophin fragment. This unique ab initio model was converted to a volume grid constraints (molecular shape) to guide the interactive flexible fitting simulations, as described in previous work (27). Dystrophin fragments homology models (with spectrin as structural pattern) were adjusted to the molecular shape by multiple interactive simulations exploring headto-tail initial positions of the protein fragment (see Supplemental Movie and Supporting Information for details).…”

Adaptive GPU-accelerated force calculation for interactive rigid molecular docking using haptics

“…of about 10ms), and computed the percentage of those responses found below 1ms, within 1-2ms(inclusive), within 2-4ms and above 4ms (Figures 7c and 7d), since there are reports suggesting that acceptable haptic refresh rates in some cases can go as low as 250-300Hz [43,44]. We report test-case/construction specific data 360 (Table 1) …”

Structural Basis of Neuronal Nitric-oxide Synthase Interaction with Dystrophin Repeats 16 and 17

“…The two dystrophin R16 -17 models used in this study were previously obtained using small-angle x-ray scattering and molecular dynamics (24). SAXS measurements were conducted at the French synchrotron SOLEIL (St. Aubin, France) on the SWING beamline.…”

“…To take into account the different secondary structural elements of nNOS-PDZ while allowing a sufficient degree of freedom for flexible docking, we chose a multiple distance cut-off to define backbone particles as previously described (24). Both proteins were converted to an augmented Elastic Network Model, which links by a spring two particles when they are closer than the cut-off distances.…”