No abstract

In the context of drug−receptor binding affinity calculations using molecular dynamics techniques, we implemented a combination of Hamiltonian replica exchange (HREM) and a novel nonequilibrium alchemical methodology, called virtual double-system single-box, with increased accuracy, precision, and efficiency with respect to the standard nonequilibrium approaches. The method has been applied for the determination of absolute binding free energies of 16 newly designed noncovalent ligands of the main protease (3CL pro ) of SARS-CoV-2. The core structures of 3CL pro ligands were previously identified using a multimodal structure-based ligand design in combination with docking techniques. The calculated binding free energies for four additional ligands with known activity (either for SARS-CoV or SARS-CoV-2 main protease) are also reported. The nature of binding in the 3CL pro active site and the involved residues besides the CYS−HYS catalytic dyad have been thoroughly characterized by enhanced sampling simulations of the bound state. We have identified several noncongeneric compounds with predicted low micromolar activity for 3CL pro inhibition, which may constitute possible lead compounds for the development of antiviral agents in Covid-19 treatment.

In this paper, we compute, by means of a non equilibrium alchemical technique, called fast switching double annihilation methods (FSDAM), the absolute standard dissociation free energies of the the octa acids host-guest systems in the SAMPL6 challenge initiative. FSDAM is based on the production of canonical configurations of the bound and unbound states via enhanced sampling and on the subsequent generation of hundreds of fast non-equilibrium ligand annihilation trajectories. The annihilation free energies of the ligand when bound to the receptor and in bulk solvent are obtained from the collection of work values using an estimate based on the Crooks theorem for driven non equilibrium processes. The FSDAM blind prediction, relying on the normality assumption for the annihilation work distributions, ranked fairly well among the submitted blind predictions that were not adjusted with a linear corrections obtained from retrospective data on similar host guest systems. Improved results for FSDAM can be obtained by post-processing the work data assuming mixtures of normal components.

ENEA is the Italian National Agency for New Technologies, Energy and Sustainable Economic Development. ENEA operates in many sectors among which the most important are: energy technologies, materials physics, life sciences and climate. In the framework of its institutional mission, the ICT Division provides computing and storage resources integrated into ENEAGRID/CRESCO, an infrastructure distributed over 6 sites, whose main facilities are the HPC CRESCO clusters. The bulk of all storage is based on IBM Spectrum Scale (GPFS) since many years. The access to data, even over WAN, is managed by GPFS clusters. In May 2018 the new cluster CRESCO6 was inaugurated. CRESCO6, a 1.4 Pflops based on Intel Xeon X86_64 SkyLake CPU ranked at 420 th of TOP 500 Nov.2018 list. While the interconnection of CRESCO6 is based on Intel Omni-Path (OPA) (100 Gbps), the previous CRESCO4 and CRESCO5 clusters have a network based on InfniBand QDR Truescale fabric (40 Gbps). Hence, in order to provides storage to all CRESCO clusters a GPFS multifabric layout has been implemented after dedicated tests. The work describes the ENEAGRID/CRESCO infrastructure and in particular the solution adopted to implement the GPFS multifabric.

In the context of the SAMPL7 challenge, we computed, employing a nonequilibrium (NE) alchemical technique, the standard binding free energy of two series of host-guest systems, involving as a host the Isaac's TrimerTrip, a Cucurbituril-like open cavitand, and the Gilson's Cyclodextrin derivatives. The adopted NE alchemy combines enhanced sampling molecular dynamics simulations with driven fast out-of-equilibrium alchemical trajectories to recover the free energy via the Jarzynski and Crooks NE theorems. The GAFF2 nonpolarizable force field was used for the parametrization. Performances were acceptable and similar in accuracy to those we submitted for Gibb's Deep Cavity Cavitands in the previous SAMPL6 host-guest challenge, confirming the reliability of the computational approach and exposing, in some cases, some important deficiencies of the GAFF2 non-polarizable force field.