Toward Accurate Post-Born-Oppenheimer Molecular Simulations on Quantum Computers: An Adaptive Variational Eigensolver with Nuclear-Electronic Frozen Natural Orbitals.

Nuclear quantum effects such as zero-point energy and hydrogen tunneling play a central role in many biological and chemical processes. The nuclear-electronic orbital (NEO) approach captures these effects by treating selected nuclei quantum mechanically on the same footing as electrons. On classical computers, the resources required for an exact solution of NEO-based models grow exponentially with system size. By contrast, quantum computers offer a means of solving this problem with polynomial scaling. However, due to the limitations of current quantum devices, NEO simulations are confined to the smallest systems described by minimal basis sets, whereas realistic simulations beyond the Born-Oppenheimer approximation require more sophisticated basis sets. For this purpose, we herein extend a hardware-efficient ADAPT-VQE method to the NEO framework in the frozen natural orbital (FNO) basis. We demonstrate on H2 and D2 molecules that the NEO-FNO-ADAPT-VQE method reduces the CNOT count by several orders of magnitude relative to the NEO unitary coupled cluster method with singles and doubles while maintaining the desired accuracy. This extreme reduction in the CNOT gate count is sufficient to permit practical computations employing the NEO method─an important step toward accurate simulations involving nonclassical nuclei and non-Born-Oppenheimer effects on near-term quantum devices. We further show that the method can capture isotope effects, and we demonstrate that inclusion of correlation energy systematically improves the prediction of difference in the zero-point energy (ΔZPE) between isotopes.

Electronic Polarizability Tunes the Function of the Human Bestrophin 1 Cl⁻ Channel.

Mechanisms of anion permeation within ion channels and nanopores remain poorly understood. Recent cryo-electron microscopy structures of the human bestrophin 1 chloride channel (hBest1) provide an opportunity to evaluate ion interactions predicted by molecular dynamics (MD) simulations against experimental observations. We implement the fully polarizable forcefield AMOEBA in MD simulations of open and partially-open states of the hBest1. The AMOEBA forcefield models multipole moments up to the quadrupole; therefore, it captures induced dipole and anion-π interactions. By including polarization we demonstrate the key role that aromatic residues play in ion permeation and the functional advantages of pore asymmetry within the highly conserved hydrophobic neck of the pore. We establish that these only arise when electronic polarization is included in the molecular models. We also show that Cl⁻ permeation in this region can be achieved through hydrophobic solvation concomitant with partial ion dehydration, which is compensated for by the formation of contacts with the edge of the phenylalanine ring. Furthermore, we demonstrate how polarizable simulations can help determine the identity of ion-like densities within high-resolution cryo-EM structures. Crucially, neglecting polarization in simulation of these systems results in the localization of Cl⁻ at positions that do not correspond with their experimentally resolved location. Overall, our results demonstrate the importance of including electronic polarization in realistic and physically accurate models of biological systems.

Structure adaptation in Omicron SARS-CoV-2/hACE2: Biophysical origins of evolutionary driving forces.

Since its emergence, the COVID-19 threat has been sustained by a series of transmission waves initiated by new variants of the SARS-CoV-2 virus. Some of these arise with higher transmissivity and/or increased disease severity. Here, we use molecular dynamics simulations to examine the modulation of the fundamental interactions between the receptor binding domain (RBD) of the spike glycoprotein and the host cell receptor (human angiotensin-converting enzyme 2 [hACE2]) arising from Omicron variant mutations (BA.1 and BA.2) relative to the original wild-type strain. Our key findings are that glycans play a vital role at the RBD···hACE2 interface for the Omicrons, and the interplay between glycans and sequence mutations leads to enhanced binding. We find significant structural differences in the complexes, which overall bring the spike protein and its receptor into closer proximity. These are consistent with and attributed to the higher positive charge on the RBD conferred by BA.1 and BA.2 mutations relative to the wild-type. However, further differences between subvariants BA.1 and BA.2 (which have equivalent RBD charges) are also evident: mutations reduce interdomain interactions between the up chain and its clockwise neighbor chain in particular for the latter, resulting in enhanced flexibility for BA.2. Consequently, we see occurrence of additional close contacts in one replica of BA.2, which include binding to hACE2 by a second RBD in addition to the up chain. Although this motif is not seen in BA.1, we find that the Omicrons can directly/indirectly bind a down-RBD to hACE2 through glycans: the role of the glycan on N90 of hACE2 switches from inhibiting to facilitating the binding to Omicron spike protein via glycan-protein lateral interactions. These structural and electrostatic differences offer further insight into the mechanisms by which viral mutations modulate host cell binding and provide a biophysical basis for evolutionary driving forces.

Nonadiabatic Nuclear-Electron Dynamics: A Quantum Computing Approach.

Coupled quantum electron-nuclear dynamics is often associated with the Born-Huang expansion of the molecular wave function and the appearance of nonadiabatic effects as a perturbation. On the other hand, native multicomponent representations of electrons and nuclei also exist, which do not rely on any a priori approximation. However, their implementation is hampered by prohibitive scaling. Consequently, quantum computers offer a unique opportunity for extending their use to larger systems. Here, we propose a quantum algorithm for simulating the time-evolution of molecular systems and apply it to proton transfer dynamics in malonaldehyde, described as a rigid scaffold. The proposed quantum algorithm can be easily generalized to include the explicit dynamics of the classically described molecular scaffold. We show how entanglement between electronic and nuclear degrees of freedom can persist over long times if electrons do not follow the nuclear displacement adiabatically. The proposed quantum algorithm may become a valid candidate for the study of such phenomena when sufficiently powerful quantum computers become available.

A quantum computing implementation of nuclearelectronic orbital (NEO) theory: Toward an exact pre-Born-Oppenheimer formulation of molecular quantum systems.

Nuclear quantum phenomena beyond the Born-Oppenheimer approximation are known to play an important role in a growing number of chemical and biological processes. While there exists no unique consensus on a rigorous and efficient implementation of coupled electron-nuclear quantum dynamics, it is recognized that these problems scale exponentially with system size on classical processors and, therefore, may benefit from quantum computing implementations. Here, we introduce a methodology for the efficient quantum treatment of the electron-nuclear problem on near-term quantum computers, based upon the Nuclear-Electronic Orbital (NEO) approach. We generalize the electronic two-qubit tapering scheme to include nuclei by exploiting symmetries inherent in the NEO framework, thereby reducing the Hamiltonian dimension, number of qubits, gates, and measurements needed for calculations. We also develop parameter transfer and initialization techniques, which improve convergence behavior relative to conventional initialization. These techniques are applied to H2 and malonaldehyde for which results agree with NEO full configuration interaction and NEO complete active space configuration interaction benchmarks for ground state energy to within 10-6 hartree and entanglement entropy to within 10-4. These implementations therefore significantly reduce resource requirements for full quantum simulations of molecules on near-term quantum devices while maintaining high accuracy.

Accelerating drug target inhibitor discovery with a deep generative foundation model.

Inhibitor discovery for emerging drug-target proteins is challenging, especially when target structure or active molecules are unknown. Here, we experimentally validate the broad utility of a deep generative framework trained at-scale on protein sequences, small molecules, and their mutual interactions-unbiased toward any specific target. We performed a protein sequence-conditioned sampling on the generative foundation model to design small-molecule inhibitors for two dissimilar targets: the spike protein receptor-binding domain (RBD) and the main protease from SARS-CoV-2. Despite using only the target sequence information during the model inference, micromolar-level inhibition was observed in vitro for two candidates out of four synthesized for each target. The most potent spike RBD inhibitor exhibited activity against several variants in live virus neutralization assays. These results establish that a single, broadly deployable generative foundation model for accelerated inhibitor discovery is effective and efficient, even in the absence of target structure or binder information.

Influence of electronic polarization on the binding of anions to a chloride-pumping rhodopsin.

The functional properties of some biological ion channels and membrane transport proteins are proposed to exploit anion-hydrophobic interactions. Here, we investigate a chloride-pumping rhodopsin as an example of a membrane protein known to contain a defined anion binding site composed predominantly of hydrophobic residues. Using molecular dynamics simulations, we explore Cl- binding to this hydrophobic site and compare the dynamics arising when electronic polarization is neglected (CHARMM36 [c36] fixed-charge force field), included implicitly (via the prosECCo force field), or included explicitly (through the polarizable force field, AMOEBA). Free energy landscapes of Cl- moving out of the binding site and into bulk solution demonstrate that the inclusion of polarization results in stronger ion binding and a second metastable binding site in chloride-pumping rhodopsin. Simulations focused on this hydrophobic binding site also indicate longer binding durations and closer ion proximity when polarization is included. Furthermore, simulations reveal that Cl- within this binding site interacts with an adjacent loop to facilitate rebinding events that are not observed when polarization is neglected. These results demonstrate how the inclusion of polarization can influence the behavior of anions within protein binding sites and can yield results comparable with more accurate and computationally demanding methods.

Influence of effective polarization on ion and water interactions within a biomimetic nanopore.

Interactions between ions and water at hydrophobic interfaces within ion channels and nanopores are suggested to play a key role in the movement of ions across biological membranes. Previous molecular-dynamics simulations have shown that anion affinity for aqueous/hydrophobic interfaces can be markedly influenced by including polarization effects through an electronic continuum correction. Here, we designed a model biomimetic nanopore to imitate the polar pore openings and hydrophobic gating regions found in pentameric ligand-gated ion channels. Molecular-dynamics simulations were then performed using both a non-polarizable force field and the electronic-continuum-correction method to investigate the behavior of water, Na+, and Cl- ions confined within the hydrophobic region of the nanopore. Number-density distributions revealed preferential Cl- adsorption to the hydrophobic pore walls, with this interfacial layer largely devoid of Na+. Free-energy profiles for Na+ and Cl- permeating the pore also display an energy-barrier reduction associated with the localization of Cl- to this hydrophobic interface, and the hydration-number profiles reflect a corresponding reduction in the first hydration shell of Cl-. Crucially, these ion effects were only observed through inclusion of effective polarization, which therefore suggests that polarizability may be essential for an accurate description for the behavior of ions and water within hydrophobic nanoscale pores, especially those that conduct Cl-.

Small molecules enhance the potency of natural antimicrobial peptides.

The skin-associated microbiome plays an important role in general well-being and in a variety of treatable skin conditions. In this regard, endogenous antimicrobial peptides have both a direct and indirect role in determining the composition of the microbiota. We demonstrate here that certain small molecular species can amplify the antimicrobial potency of naturally occurring antimicrobial peptides. In this study, we have used niacinamide, a form of vitamin B3 naturally found in foods and widely used in cosmetic skincare products, and two of its structural analogs, to investigate their cooperativity with the human antimicrobial peptide LL37 on the bacterium Staphylococcus aureus. We observed a clear synergistic effect of niacinamide and, to some extent, N-methylnicotinamide, whereas isonicotinamide showed no significant cooperativity with LL37. Adaptively biased molecular dynamics simulations using simplified model membrane substrates and single peptides revealed that these molecules partition into the headgroup region of an anionic bilayer used to mimic the bacterial membrane. The simulated effects on the physical properties of the simulated model membrane are well correlated with experimental activity observed in real biological assays despite the simplicity of the model. In contrast, these molecules have little effect on zwitterionic bilayers that mimic a mammalian membrane. We conclude that niacinamide and N-methylnicotinamide can therefore potentiate the activity of host peptides by modulating the physical properties of the bacterial membrane, and to a lesser extent through direct interactions with the peptide. The level of cooperativity is strongly dependent on the detailed chemistry of the additive, suggesting an opportunity to fine-tune the behavior of host peptides.

Switching Cytolytic Nanopores into Antimicrobial Fractal Ruptures by a Single Side Chain Mutation.

Disruption of cell membranes is a fundamental host defense 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 nonhemolytic. The results offer wide implications for elucidating differential membrane targeting phenomena defined at the nanoscale.

Accelerated antimicrobial discovery via deep generative models and molecular dynamics simulations.

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.

Membrane Binding of Antimicrobial Peptides Is Modulated by Lipid Charge Modification.

Peptide interactions with lipid bilayers play a key role in a range of biological processes and depend on electrostatic interactions between charged amino acids and lipid headgroups. Antimicrobial peptides (AMPs) initiate the killing of bacteria by binding to and destabilizing their membranes. The multiple peptide resistance factor (MprF) provides a defense mechanism for bacteria against a broad range of AMPs. MprF reduces the negative charge of bacterial membranes through enzymatic conversion of the anionic lipid phosphatidyl glycerol (PG) to either zwitterionic alanyl-phosphatidyl glycerol (Ala-PG) or cationic lysyl-phosphatidyl glycerol (Lys-PG). The resulting change in the membrane charge is suggested to reduce the binding of AMPs to membranes, thus impeding downstream AMP activity. Using coarse-grained molecular dynamics to investigate the effects of these modified lipids on AMP binding to model membranes, we show that AMPs have substantially reduced affinity for model membranes containing Ala-PG or Lys-PG. More than 5000 simulations in total are used to define the relationship between lipid bilayer composition, peptide sequence (using five different membrane-active peptides), and peptide binding to membranes. The degree of interaction of a peptide with a membrane correlates with the membrane surface charge density. Free energy profile (potential of mean force) calculations reveal that the lipid modifications due to MprF alter the energy barrier to peptide helix penetration of the bilayer. These results will offer a guide to the design of novel peptides, which addresses the issue of resistance via MprF-mediated membrane modification.

Membrane Permeability in Cyclic Peptides is Modulated by Core Conformations.

Cyclic peptides have the potential to bind to challenging targets, which are undruggable with small molecules, but their application is limited by low membrane permeability. Here, using a series of cyclic pentapeptides, we showed that established physicochemical criteria of permeable peptides are heavily violated. We revealed that a dominant core conformation, stabilized by amides' shielding pattern, could guide the design of novel compounds. As a result, counter-intuitive strategies, such as incorporation of polar residues, can be beneficial for permeability. We further find that core globularity is a promising descriptor, which can extend the capability of standard predictive models.

Network Topology in Water Nanoconfined between Phospholipid Membranes.

Water provides the driving force for the assembly and stability of many cellular components. Despite its impact on biological functions, a nanoscale understanding of the relationship between its structure and dynamics under soft confinement has remained elusive. As expected, water in contact with biological membranes recovers its bulk density and dynamics at ∼1 nm from phospholipid headgroups but surprisingly enhances its intermediate range order (IRO) over a distance, at least, twice as large. Here, we explore how the IRO is related to the water's hydrogen-bond network (HBN) and its coordination defects. We characterize the increased IRO by an alteration of the HBN up to more than eight coordination shells of hydration water. The HBN analysis emphasizes the existence of a bound-unbound water interface at ∼0.8 nm from the membrane. The unbound water has a distribution of defects intermediate between bound and bulk water, but with density and dynamics similar to bulk, while bound water has reduced thermal energy and many more HBN defects than low-temperature water. This observation could be fundamental for developing nanoscale models of biological interactions and for understanding how alteration of the water structure and topology, for example, due to changes in extracellular ions concentration, could affect diseases and signaling. More generally, it gives us a different perspective to study nanoconfined water.

Modulation of Antimicrobial Peptide Potency in Stressed Lipid Bilayers.

It is shown that the tendency of an archetypal antimicrobial peptide to insert into and perforate a simple lipid bilayer is strongly modulated by tensile stress in the membrane. The results, obtained through molecular dynamics simulations, have been demonstrated with several lipid compositions and appear to be general, although quantitative details differ. The findings imply that the potency of antimicrobial peptides may not be a purely intrinsic chemical property and, instead, depends on the mechanical state of the target membrane.

Author Correction: Tuneable poration: host defense peptides as sequence probes for antimicrobial mechanisms.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Tuneable poration: host defense peptides as sequence probes for antimicrobial mechanisms.

The spread of antimicrobial resistance stimulates discovery strategies that place emphasis on mechanisms circumventing the drawbacks of traditional antibiotics and on agents that hit multiple targets. Host defense peptides (HDPs) are promising candidates in this regard. Here we demonstrate that a given HDP sequence intrinsically encodes for tuneable mechanisms of membrane disruption. Using an archetypal HDP (cecropin B) we show that subtle structural alterations convert antimicrobial mechanisms from native carpet-like scenarios to poration and non-porating membrane exfoliation. Such distinct mechanisms, studied using low- and high-resolution spectroscopy, nanoscale imaging and molecular dynamics simulations, all maintain strong antimicrobial effects, albeit with diminished activity against pathogens resistant to HDPs. The strategy offers an effective search paradigm for the sequence probing of discrete antimicrobial mechanisms within a single HDP.

Accelerating molecular discovery through data and physical sciences: Applications to peptide-membrane interactions.

Simulation and data analysis have evolved into powerful methods for discovering and understanding molecular modes of action and designing new compounds to exploit these modes. The combination provides a strong impetus to create and exploit new tools and techniques at the interfaces between physics, biology, and data science as a pathway to new scientific insight and accelerated discovery. In this context, we explore the rational design of novel antimicrobial peptides (short protein sequences exhibiting broad activity against multiple species of bacteria). We show how datasets can be harvested to reveal features which inform new design concepts. We introduce new analysis and visualization tools: a graphical representation of the k-mer spectrum as a fundamental property encoded in antimicrobial peptide databases and a data-driven representation to illustrate membrane binding and permeation of helical peptides.

Cooperative Modes of Action of Antimicrobial Peptides Characterized with Atomistic Simulations: A Study on Cecropin B.

Antimicrobial peptides (AMPs) are widely occurring host defense agents of interest as one route for addressing the growing problem of multidrug-resistant pathogens. Understanding the mechanisms behind their antipathogen activity is instrumental in designing new AMPs. Herein, we present an all-atom molecular dynamics and free energy study on cecropin B (CB) and its constituent domains. We find a cooperative mechanism in which CB inserts into an anionic model membrane with its amphipathic N-terminal segment, supported by the hydrophobic C-terminal segment of a second peptide. The two peptides interact via a Glu···Lys salt bridge and together sustain a pore in the membrane. Using a modified membrane composition, we demonstrate that when the lower leaflet is overall neutral, insertion of the cationic segment is retarded and thus this mode of action is membrane specific. The observed mode of action utilizes a flexible hinge, a common structural motif among AMPs, which allows CB to insert into the membrane using either or both termini. Data from both unbiased trajectories and enhanced sampling simulations indicate that a requirement for CB to be an effective AMP is the interaction of its hydrophobic C-terminal segment with the membrane. Simulations of these segments in isolation reveal their aggregation in the membrane and a different mechanism of supporting pore formation. Together, our results show the complex interaction of different structural motifs of AMPs and, in particular, a potential role for electronegative side chains in an overall cationic AMP.