Perspectives on High-Throughput Ligand/Protein Docking With Martini MD Simulations

Abstract

Molecular docking is central to rational drug design. Current docking techniques suffer, however, from limitations in protein flexibility and solvation models and by the use of simplified scoring functions. All-atom molecular dynamics simulations, on the other hand, feature a realistic representation of protein flexibility and solvent, but require knowledge of the binding site. Recently we showed that coarse-grained molecular dynamics simulations, based on the most recent version of the Martini force field, can be used to predict protein/ligand binding sites and pathways, without requiring any a priori information, and offer a level of accuracy approaching all-atom simulations. Given the excellent computational efficiency of Martini, this opens the way to high-throughput drug screening based on dynamic docking pipelines. In this opinion article, we sketch the roadmap to achieve this goal.

Targeting the energy-coupling factor (ECF) transporters: identification of new tool compounds

“…This complete view including protein flexibility, and competition between environments and (hidden) protein pockets can only be properly estimated in the MD simulations as they consider all of these effects. 33 Additional redocking calculations (starting from relaxed configurations from the simulations) performed now in P2, P9 and P11, did not provide new evidence for the preference for P9 in relation to the other pockets (Figure S32, Table S4). However, future experimental evidence is still necessary to confirm the binding pocket and provide the complete molecular mechanism involved in the inhibition of the ECF transporters promoted by our newly discovered compounds.…”

Understanding insulin and its receptor from their three-dimensional structures

“…It has also been used to investigate the engagement of novel insulins with the receptor sites described above [ 120 ]. Computational techniques to model the trajectories of the large-scale domain motion that occurs within the receptor as whole upon ligand binding may also become within reach [ [121] , [122] , [123] ]. The next step forward is likely to occur within years, not decades.…”

Martini 3 Coarse-Grained Force Field: Small Molecules

“…The present database, along with the outlined model design strategies and the modularity of the Martini force field, constitute a resource of models that 1) can be used "as is" in (bio)molecular simulations; 2) gives reference points for the construction of other small molecule models; 3) provides guidelines and reference data for automated topology builders; and 4) can be used as building blocks for the construction of more complex (macro)molecules, hence enabling investigations of complex biomolecular 21,71 and soft material systems. 10,72…”

“…On the biomolecular side, a natural application of the small molecules presented here combined with the Martini protein models 24 is to investigate protein-ligand interactions in unbiased or biased MD simulations. 21,71 The parametrization guidelines and strategies are expected to facilitate the building of databases with accurate Martini 3 models of small molecules; this possibly will require the help of the next-generation of programs aimed at automated topology building of Martini models, 12,26 and automated parametrization of bonded parameters. 25,27 On the materials science side, Martini 3 and the presented parametrization guidelines are expected to open up the possibility of more easily model organic functional materials in general.…”