posted on 2020-09-02, 20:45authored byTharindu Senapathi, Miroslav Suruzhon, Christopher B. Barnett, Jonathan Essex, Kevin J. Naidoo
Biomolecular
Reaction and Interaction Dynamics Global Environment
(BRIDGE) is an open-source web platform developed with the aim to
provide an environment for the design of reliable methods to conduct
reproducible biomolecular simulations. It is built on the well-known
Galaxy bioinformatics platform. Through this, BRIDGE hosts computational
chemistry tools on public web servers for internet use and provides
machine- and operating-system-independent portability using the Docker
container platform for local use. This construction improves the accessibility,
shareability, and reproducibility of computational methods for molecular
simulations. Here we present integrated free energy tools (or apps)
to calculate absolute binding free energies (ABFEs) and relative binding
free energies (RBFEs), as illustrated through use cases. We present
free energy perturbation (FEP) methods contained in various software
packages such as GROMACS and YANK that are independent of hardware
configuration, software libraries, or operating systems when ported
in the Galaxy-BRIDGE Docker container platform. By performing cyclin-dependent
kinase 2 (CDK2) FEP calculations on geographically dispersed web servers
(in Africa and Europe), we illustrate that large-scale computations
can be performed using the exact same codes and methodology by collaborating
groups through publicly shared protocols and workflows. The ease of
public sharing and independent reproduction of simulations via BRIDGE
makes possible an open review of methods and complete simulation protocols.
This makes the discovery of inhibitors for drug targets accessible
to nonexperts and the computer experiments that are used to arrive
at leads verifiable by experts and reviewers. We illustrate this on
β-galactoside α-2,3-sialyltransferase I (ST3Gal-I), a
breast cancer drug target, where a combination of RBFE and ABFE methods
are used to compute the binding free energies of three inhibitors.