Antimicrobial peptides emerge as compounds that can alleviate the global health hazard of antimicrobial resistance, prompting a need for novel computational approaches to peptide generation. Here, we propose HydrAMP, a conditional variational autoencoder that learns lower-dimensional, continuous representation of peptides and captures their antimicrobial properties. The model disentangles the learnt representation of a peptide from its antimicrobial conditions and leverages parameter-controlled creativity. HydrAMP is the first model that is directly optimized for diverse tasks, including unconstrained and analogue generation and outperforms other approaches in these tasks. An additional preselection procedure based on ranking of generated peptides and molecular dynamics simulations increases experimental validation rate. Wet-lab experiments on five bacterial strains confirm high activity of nine peptides generated as analogues of clinically relevant prototypes, as well as six analogues of an inactive peptide. HydrAMP enables generation of diverse and potent peptides, making a step towards resolving the antimicrobial resistance crisis.

Topological analysis of the electron localisation function (ELF), natural bond orbital and Wiberg bond index calculations have been applied to study the electronic structure of the oxaziridine molecule with a special focus on the nitrogen-oxygen bond. The calculations have been performed at the DFT(B3LYP, CAM-B3LYP, ωB97XD, M06-L, M06-2X) and post-Hartree-Fock (CCSD(T) and CASSCF) computational levels with applied aug-cc-pVTZ basis set. Nature of N-O bonding has been characterised by two resonance forms, N⁺O⁻ and N⁻O⁺, owing to a very small population (< 0.60e) of the bonding basin V(N,O), localised in the ELF field for the N-O region. The importance of electron correlation effects for the description of the N-O bonding has been observed in the CASSCF calculations. The orbital description (Wiberg, NBO) differs from topological characterisation, indicating a single N-O bond.

The local electronic structure of the Al=Al bond was studied in dialumene and derivatives of dialumene in which the Al atoms were substituted by B, Ga, or In atoms. DFT calculations were performed using the B3LYP, B3PW91, PBE0, M06-L, and M06-2X functionals. Topological analysis of the electron localization function described the covalent bonds mentioned above using the disynaptic basins V_i=1,2(B,B), V_i=1,2(Al,Al), V(Ga,Ga), and V_i=1,2(In,In). The basin populations were smaller than 4 e, as expected for a double bond: B=B 2.97 e, Al=Al 3.44–3.5 e, Ga=Ga 3.58 e, and In=In 3.86 e. The Al=Al, Ga=Ga, and In=In bonds were found to be intermediate in character between single and double bonds. Topological analysis of the ρ(r) field for dialumene showed a non-nuclear attractor along the Al=Al bond, with a pseudoatom basin population of 0.937 e. NBO analysis suggested that a double bond occurred only in the molecules containing Al, Ga, or In atoms. The character of the Ga=Ga bond was observed to be strongly dependent on the effective core potential used in the calculations.

Photoswitchable diarylethenes (DAEs), over years of intense fundamental and applied research, have been established among the most commonly chosen molecular photoswitches, often employed as controlling units in molecular devices and smart materials. At the same time, providing reliable explanation for their photophysical behavior, especially the mechanism of the photo-cycloreversion transformation, turned out to be a highly challenging task. Herein, we investigate this mechanism in detail by means of multireference semi-empirical quantum chemistry calculations, allowing, for the first time, for a balanced treatment of the static and dynamic correlation effects, both playing a crucial role in DAE photochemistry. In the course of our study, we find the second singlet excited state of double electronic-excitation character to be the key to understanding the nature of the photo-cycloreversion transformation in DAE molecular photoswitches.

The entry of influenza virus into the host cell requires fusion of its lipid envelope with the host membrane. It is catalysed by viral hemagglutinin protein, whose fragments called fusion peptides become inserted into the target bilayer and initiate its merging with the viral membrane. Isolated fusion peptides are already capable of inducing lipid mixing between liposomes. Years of studies indicate that upon membrane binding they form bend helical structure whose degree of opening fluctuates between tightly closed hairpin and an extended boomerang. The actual way in which they initiate fusion remains elusive. In this work we employ atomistic simulations of wild type and fusion inactive W14A mutant of influenza fusion peptides confined between two closely apposed lipid bilayers. We characterise peptide induced membrane perturbation and determine the potential of mean force for the formation of the first fusion intermediate, an interbilayer lipid bridge called stalk. Our results demonstrate two routes through which the peptides can lower free energy barrier towards fusion. The first one assumes peptides capability to adopt transmembrane configuration which subsequently promotes the creation of a stalk-hole complex. The second involves surface bound peptide configuration and proceeds owing to its ability to stabilise stalk by fitting into the region of extreme negative membrane curvature resulting from its formation. In both cases, the active peptide conformation corresponds to tight helical hairpin, whereas extended boomerang geometry appears to be unable to provide favourable thermodynamic effect. The latter observation offers plausible explanation for long known inactivity of boomerang-stabilising W14A mutation.