Biomolecular simulations are revealing mechanisms of enzyme catalysis and inhibition, dynamics and thermodynamics relevant to function, and are contributing to catalyst and inhibitor design. Simulations can be used as computational ‘assays’ of biological activity, e.g. to predict drug resistance or the effects of mutation [1]. Different types of application require different levels of treatment, which can be combined in multiscale models to tackle a range of time- and length-scales [2,3]. Molecular simulation methods of various types are now capable of modelling processes ranging from biochemical reactions to membrane dynamics, and can offer increasing predictive power. Recently, this has included identifying important features of SARS-CoV-2 proteins, such as the effects of linoleate on the viral Spike protein [4,5].
Dynamical-nonequilibrium molecular dynamics (D-NEMD) simulations [6] reveal allosteric coupling of the fatty acid binding site to distant functional regions in the Spike, such as the furin cleavage site [5]. D-NEMD simulations also show coupling between allosteric sites and the active site in beta-lactamase enzymes; the pathways identified contain positions that differ between clinically relevant variants of these enzymes, indicating that allosteric effects modulate the spectrum of activity of these antibiotic resistance enzymes [7].
Combined quantum mechanics/molecular mechanics (QM/MM) methods allow modelling of reactions in proteins: they can identify mechanisms of reaction (e.g. for targeted covalent inhibitors such as ibrutinib [8]) and determinants of catalytic activity [9] and drug resistance [10]; and predict the activity of bacterial enzymes against antibiotics.
Increasingly, simulations are contributing to the engineering of natural enzymes, and to design and development of de novo biocatalysts [11]. Simulations are also contributing to the emerging evidence that activation heat capacity is an important factor in enzyme evolution and thermoadaptation [12,13]. Directed evolution of the catalytic activity of a designed Kemp eliminase unexpectedly introduced curvature into the temperature dependence of catalysis, a signature of the appearance of an activation heat capacity [14]. Simulations identify the dynamical networks involved, which may provide useful targets for mutation [15].
Virtual reality offers new ways interact with simulations, and new ways to collaborate [16,17]. Interactive MD simulation in virtual reality (iMD-VR) allows direct manipulation of biological macromolecules, going beyond mere visualization to allow e.g. fully flexible docking of drugs into protein targets [18,19]. The COVID-19 pandemic has highlighted the need for effective tools for virtual collaboration in VR. Groups of researchers can work together in the same virtual environment, using iMD-VR for molecular problems such as catalyst and structure-based drug design. These simulation methods, including iMD-VR, with collaborative sharing of models and data, have been brought together to develop peptide inhibitors of the SARS-CoV-2 main protease [20].