Ab initio molecular dynamics (MD) with hybrid density functionals and a plane wave basis is computationally expensive due to the high computational cost of exact exchange energy evaluation. Recently, we proposed a strategy to combine adaptively compressed exchange (ACE) operator formulation and a multiple time step integration scheme to reduce the computational cost significantly [J. Chem. Phys. 2019, 151, 151102 ]. However, it was found that the construction of the ACE operator, which has to be done at least once in every MD time step, is computationally expensive. In the present work, systematic improvements are introduced to further speed up by employing localized orbitals for the construction of the ACE operator. By this, we could achieve a computational speedup of an order of magnitude for a periodic system containing 32 water molecules. Benchmark calculations were carried out to show the accuracy and efficiency of the method in predicting the structural and dynamical properties of bulk water. To demonstrate the applicability, computationally intensive freeenergy computations at the level of hybrid density functional theory were performed to investigate (a) methyl formate hydrolysis reaction in neutral aqueous media and (b) proton-transfer reaction within the active-site residues of the class C β-lactamase enzyme.

Escalation of antibiotic resistance due to class D β-lactamases (DBLs) carrying bacteria is a matter of grave concern. This class of enzymes can efficiently hydrolyze the carbapenem group of antibiotics that are the last-reserved therapeutics for infections caused by multidrug-resistant bacteria. The development of efficient inhibitors against DBLs calls for a molecular-level understanding of the hydrolysis mechanism. Here, we investigate the mechanism of inhibition of OXA-48 DBL enzyme by one of the diazobicyclooctane class of inhibitors, namely avibactam, through molecular dynamics simulations and free energy calculations. Hydrolysis as well as inhibition mechanisms are expected to be intricate due to the presence of N-carbamylated lysine (Lys73), multiple acidic and basic active site residues, and active site water molecules. Our extensive mechanistic study characterizes the most probable reaction route and critical reaction intermediates starting from the acylation to the full hydrolysis of the covalent intermediate. This study discerns the residues that act as the general bases at different steps. Free energies and reaction intermediate structures are corroborated with the available experimental kinetics data and crystal structures. We also simulated the deacylation of a β-lactam drug, namely meropenem, which is known to be hydrolyzed efficiently by the enzyme. By comparing the mechanism of meropenem hydrolysis with that of avibactam, our study reveals the important chemical features that are useful for designing inhibitors.

Ab initio molecular dynamics (AIMD) with hybrid density functionals and plane wave basis is computationally expensive due to the high computational cost of exact exchange energy evaluation. Recently, we proposed a strategy to combine adaptively compressed exchange (ACE) operator formulation and multiple time step (MTS) integration scheme to reduce the computational cost significantly [J. Chem. Phys. 151, 151102 (2019)]. However, it was found that the construction of the ACE operator, which has to be done at least once in every MD time step, is computationally expensive. In the present work, systematic improvements are introduced to further speed-up by employing localized orbitals for the construction of the ACE operator. By this, we could achieve a computational speed-up of an order of magnitude for a periodic system containing 32-water molecules. Benchmark calculations were carried out to show the accuracy and efficiency of the method in predicting the structural and dynamical properties of bulk water. To demonstrate the applicability, computationally intensive free energy computations at the level of hybrid density functional theory were performed to investigate (a) methyl formate hydrolysis reaction in neutral aqueous medium and (b) proton transfer reaction within the active site residues of class-C β-lactamase enzyme.