The de novo design of antimicrobial therapeutics involves the exploration of a vast chemical repertoire to find compounds with broad-spectrum potency and low toxicity. Here, we report an efficient computational method for the generation of antimicrobials with desired attributes. The method leverages guidance from classifiers trained on an informative latent space of molecules modelled using a deep generative autoencoder, and screens the generated molecules using deep-learning classifiers as well as physicochemical features derived from high-throughput molecular dynamics simulations. Within 48 days, we identified, synthesized and experimentally tested 20 candidate antimicrobial peptides, of which two displayed high potency against diverse Gram-positive and Gram-negative pathogens (including multidrug-resistant Klebsiella pneumoniae) and a low propensity to induce drug resistance in Escherichia coli. Both peptides have low toxicity, as validated in vitro and in mice. We also show using live-cell confocal imaging that the bactericidal mode of action of the peptides involves the formation of membrane pores. The combination of deep learning and molecular dynamics may accelerate the discovery of potent and selective broad-spectrum antimicrobials.

We determine the molecular structure and orientation at the liquid-vapour interface of water using an electronically coarse grained model constructed to include all long-range electronic responses within Gaussian statistics. The model, fit to the properties of the isolated monomer and dimer, is sufficiently responsive to generate the temperature dependence of the surface tension from ambient conditions to the critical point. Acceptor hydrogen bonds are shown to be preferentially truncated at the free surface under ambient conditions and a related asymmetry in hydrogen bonding preference is identified in bulk water. We speculate that this bonding asymmetry in bulk water is the microscopic origin of the observed surface structure.

We introduce an electronically coarse-grained description of water representing all long range, many-body electronic responses via an embedded quantum oscillator. Leading-order response coefficients and gas phase electrostatic moments are exactly reproduced. Molecular dynamics, using electronic path integral sampling, shows that this framework is sufficient for a realistic liquid to emerge naturally with transferability extending further to nonambient state points and to the free water surface. The model allows the strength of many-body dispersion and polarization to be adjusted independently and these are found to have significant effects on the condensed phase.

Water challenges our fundamental understanding of emergent materials properties from a molecular perspective. It exhibits a uniquely rich phenomenology including dramatic variations in behavior over the wide temperature range of the liquid into water's crystalline phases and amorphous states. We show that many-body responses arising from water's electronic structure are essential mechanisms harnessed by the molecule to encode for the distinguishing features of its condensed states. We treat the complete set of these many-body responses nonperturbatively within a coarse-grained electronic structure derived exclusively from single-molecule properties. Such a "strong coupling" approach generates interaction terms of all symmetries to all orders, thereby enabling unique transferability to diverse local environments such as those encountered along the coexistence curve. The symmetries of local motifs that can potentially emerge are not known a priori. Consequently, electronic responses unfiltered by artificial truncation are then required to embody the terms that tip the balance to the correct set of structures. Therefore, our fully responsive molecular model produces, a simple, accurate, and intuitive picture of water's complexity and its molecular origin, predicting water's signature physical properties from ice, through liquid-vapor coexistence, to the critical point.subcritical water | intermolecular interactions | many-body dispersion | coarse-grained model | electronic responses W ater is a ubiquitous yet unusual substance exhibiting anomalous physical properties for a liquid and forming many crystalline ices and (at least) two distinct amorphous states of different density (1). As the biological solvent, it is critical that water molecules form a liquid over a very wide range of temperatures (2) and pressures (3, 4) to support life under a wide variety of conditions. Indeed, water's simple molecular structure, a three-atom, twospecies moiety, yields a surprisingly rich phenomenology in its condensed phases.It is well-known that many signature properties of water have their molecular origin in the hydrogen-bonding interactions between molecules (5, 6). These directional networks are also the source of enhanced molecular polarization in the liquid state relative to the gas (7). In addition, there is speculation that dispersion interactions which arise from quantum-mechanical fluctuations of the charge density are also an important factor in the equilibrium properties of the ambient liquid (8, 9). The question of the ranges of temperature and density where these interactions influence observable properties is important for the construction of a conceptually simple but broadly transferable physical model linking molecular and condensed phase properties with the minimum of additional assumptions. Liquid water exhibits anomalies at both extremes of temperature--including a point of maximum density near freezing, an unusually high critical temperature relative to other hydrides, and significant changes in physical pr...

Disruption of cell membranes is a fundamental host defence response found in virtually all forms of life. The molecular mechanisms vary but generally lead to energetically favored circular nanopores. Here we report an elaborate fractal rupture pattern induced by a single side-chain mutation in ultrashort (8-11-mers) helical peptides, which otherwise form transmembrane pores. In contrast to known mechanisms, this mode of membrane disruption is restricted to the upper leaflet of the bilayer where it exhibits propagating fronts of peptide-lipid interfaces that are strikingly similar to viscous instabilities in fluid flow. The two distinct disruption modes, pores and fractal patterns, are both strongly antimicrobial but only the fractal rupture is non-hemolytic. The results offer wide implications for elucidating differential membrane targeting phenomena defined at the nanoscale.