Structure of the Bacterial Cell Envelope and Interactions with Antimicrobials: Insights from Molecular Dynamics Simulations.

Bacteria have evolved over 3 billion years, shaping our intrinsic and symbiotic coexistence with these single-celled organisms. With rising populations of drug-resistant strains, the search for novel antimicrobials is an ongoing area of research. Advances in high-performance computing platforms have led to a variety of molecular dynamics simulation strategies to study the interactions of antimicrobial molecules with different compartments of the bacterial cell envelope of both Gram-positive and Gram-negative species.

Martini-3 Coarse-Grained Models for the Bacterial Lipopolysaccharide Outer Membrane of .

The outer lipopolysaccharide (LPS) membrane of Gram-negative bacteria forms the main barrier for transport of antimicrobial molecules into the bacterial cell. In this study we develop coarse-grained models for the outer membrane of in the Martini-3 framework. The coarse-grained model force field was parametrized and validated using all-atom simulations of symmetric membranes of lipid A and rough LPS as well as a complete asymmetric membrane of LPS with the O-antigen.

Differentiating interactions of antimicrobials with Gram-negative and Gram-positive bacterial cell walls using molecular dynamics simulations.

Developing molecular models to capture the complex physicochemical architecture of the bacterial cell wall and to study the interaction with antibacterial molecules is an important aspect of assessing and developing novel antimicrobial molecules. We carried out molecular dynamics simulations using an atomistic model of peptidoglycan to represent the architecture for Gram-positive S. aureus.

Interactions of Surfactants with the Bacterial Cell Wall and Inner Membrane: Revealing the Link between Aggregation and Antimicrobial Activity.

Surfactants with their intrinsic ability to solubilize lipid membranes are widely used as antibacterial agents, and their interactions with the bacterial cell envelope are complicated by their differential aggregation tendencies. We present a combined experimental and molecular dynamics investigation to unravel the molecular basis for the superior antimicrobial activity and faster kill kinetics of shorter-chain fatty acid surfactant, laurate, when compared with the longer-chain surfactants studied in contact time assays with live (). From all-atom molecular dynamics simulations, translocation events across peptidoglycan were the highest for laurate followed by sodium dodecyl sulfate, myristate, palmitate, oleate, and stearate.

A generic force field for simulating native protein structures using dissipative particle dynamics.

A coarse-grained force field for molecular dynamics simulations of the native structures of proteins in a dissipative particle dynamics (DPD) framework is developed. The parameters for bonded interactions are derived by mapping the bonds and angles for 20 amino acids onto target distributions obtained from fully atomistic simulations in explicit solvent. A dual-basin potential is introduced for stabilizing backbone angles, to cover a wide spectrum of protein secondary structures.

Developing a Coarse-Grained Model for Bacterial Cell Walls: Evaluating Mechanical Properties and Free Energy Barriers.

The bacterial cell envelope of Gram-negative bacteria is a complex biological barrier with multiple layers consisting of the inner membrane, periplasm of peptidoglycan, and the outer membrane with lipopolysaccharides (LPS). With rising antimicrobial resistance there is increasing interest in understanding interactions of small molecules with the cell membrane to aid in the development of novel drug molecules. Hence suitable representations of the bacterial membrane are required to carry out meaningful molecular dynamics simulations.

Establishing an Electrostatics Paradigm for Membrane Electroporation in the Framework of Dissipative Particle Dynamics.

With an exclusive aim to looking into a mechanism of membrane electroporation on mesoscopic length and time scales, we report the dissipative particle dynamics (DPD) simulation results for systems with and without electrolytes. A polarizable DPD model of water is employed for accurate modeling of long-range electrostatics near the water-lipid interfaces. A great deal of discussion on field induced change in dipole moments of water and lipids together with the special variation of electric field is made in order to understand the dielectrophoretic movement of water, initiating a pore formation via an intrusion through the bilayer core.

Electroporation Using Dissipative Particle Dynamics with a Novel Protocol for Applying Electric Field.

In molecular dynamics simulations of membrane electroporation, the bilayer is subjected to an electric field E either by direct addition of a force f = qE on the charge-bearing species or by imposing an ion imbalance in the salt solutions on the two sides of the bilayer. The former is believed to mimic electroporation with high fields over nanosecond pulse period, during which the membrane is almost uncharged, especially in the low salt limit. Conversely, the ion imbalance method elucidates a low electric field-induced poration over a longer period of micro- to milliseconds with a fully charged membrane.

Electrostatic interactions in dissipative particle dynamics-Ewald-like formalism, error analysis, and pressure computation.

An accurate time evolution of charged species having exponentially smeared out charge density (Slater type charge distribution) in dissipative particle dynamic (DPD) simulations necessitates the optimal choice of the Ewald splitting parameter (α), charge smearing length (λ), and real space cutoff (c) when the Ewald summation or its variant such as particle-particle particle-mesh or particle-mesh Ewald is employed for long range electrostatics. The present article offers the error estimates in the electrostatic energy and the force as a function of α and β(1/λ) on account of spherical truncation c in real space. These error estimate formulae are validated by our DPD simulation results.