Role of Peptide Associations in Enhancing the Antimicrobial Activity of Adepantins: Comparative Molecular Dynamics Simulations and Design Assessments.

Adepantins are peptides designed to optimize antimicrobial biological activity through the choice of specific amino acid residues, resulting in helical and amphipathic structures. This paper focuses on revealing the atomistic details of the mechanism of action of Adepantins and aligning design concepts with peptide behavior through simulation results. Notably, Adepantin-1a exhibits a broad spectrum of activity against both Gram-positive and Gram-negative bacteria, while Adepantin-1 has a narrow spectrum of activity against Gram-negative bacteria.

Theoretical Improvements in Enzyme Efficiency Associated with Noisy Rate Constants and Increased Dissipation.

Previous studies have revealed the extraordinarily large catalytic efficiency of some enzymes. High catalytic proficiency is an essential accomplishment of biological evolution. Natural selection led to the increased turnover number, k, and enzyme efficiency, k/K, of uni-uni enzymes, which convert a single substrate into a single product.

Designed Multifunctional Peptides for Intracellular Targets.

Nature's way for bioactive peptides is to provide them with several related functions and the ability to cooperate in performing their job. Natural cell-penetrating peptides (CPP), such as penetratins, inspired the design of multifunctional constructs with CPP ability. This review focuses on known and novel peptides that can easily reach intracellular targets with little or no toxicity to mammalian cells.

The Spectrum of Design Solutions for Improving the Activity-Selectivity Product of Peptide Antibiotics against Multidrug-Resistant Bacteria and Prostate Cancer PC-3 Cells.

The link between the antimicrobial and anticancer activity of peptides has long been studied, and the number of peptides identified with both activities has recently increased considerably. In this work, we hypothesized that designed peptides with a wide spectrum of selective antimicrobial activity will also have anticancer activity, and tested this hypothesis with newly designed peptides. The spectrum of peptides, used as partial or full design templates, ranged from cell-penetrating peptides and putative bacteriocin to those from the simplest animals (placozoans) and the Chordata phylum (anurans).

Maximum Entropy Production Theorem for Transitions between Enzyme Functional States and Its Applications.

Transitions between enzyme functional states are often connected to conformational changes involving electron or proton transport and directional movements of a group of atoms. These microscopic fluxes, resulting in entropy production, are driven by non-equilibrium concentrations of substrates and products. Maximal entropy production exists for any chosen transition, but such a maximal transitional entropy production (MTEP) requirement does not ensure an increase of total entropy production, nor an increase in catalytic performance.

Design of α-helical antimicrobial peptides with a high selectivity index.

: Low-molecular-weight antibiotics are gradually rendered ineffective by multidrug-resistant bacteria. Promising replacements are fast-acting antimicrobial peptides, either found as host defense peptides or designed, but their main weakness in applications is low selectivity for bacterial cells. : This paper explores how much human design has improved the evolutionary design for linear alpha-class antimicrobial peptides with a selective antibacterial activity.

The maximum entropy production requirement for proton transfers enhances catalytic efficiency for β-lactamases.

Movement of charges during enzyme catalytic cycle may be due to conformational changes, or to fast electron or proton transfer, or to both events. In each case, entropy production can be calculated using Terrel L. Hill's method, if relevant microscopic rate constants are known.

Designed peptide with a flexible central motif from ranatuerins adapts its conformation to bacterial membranes.

The long-standing goal in the field of peptide antibiotics has been to design lead compounds that have a wide spectrum of excellent antibacterial activity but are nontoxic to human cells. Gram-negative and Gram-positive bacteria have very different membranes, which are additionally modified in some drug-resistant species, presenting a challenge for the design of a single membrane-active peptide able to adapt its conformation to various physical properties of membrane microenvironments. In this paper, we describe how a peptide sequence can be constructed starting from an adaptable dynamic turn tandem motif in a central location.

Antibacterial Activity Affected by the Conformational Flexibility in Glycine-Lysine Based α-Helical Antimicrobial Peptides.

Antimicrobial peptides often show broad-spectrum activity due to a mechanism based on bacterial membrane disruption, which also reduces development of permanent resistance, a desirable characteristic in view of the escalating multidrug resistance problem. Host cell toxicity however requires design of artificial variants of natural AMPs to increase selectivity and reduce side effects. Kiadins were designed using rules obtained from natural peptides active against E.

Is the catalytic activity of triosephosphate isomerase fully optimized? An investigation based on maximization of entropy production.

Triosephosphate isomerase (TIM) is often described as a fully evolved housekeeping enzyme with near-maximal possible reaction rate. The assumption that an enzyme is perfectly evolved has not been easy to confirm or refute. In this paper, we use maximization of entropy production within known constraints to examine this assumption by calculating steady-state cyclic flux, corresponding entropy production, and catalytic activity in a reversible four-state scheme of TIM functional states.

Tools for Designing Amphipathic Helical Antimicrobial Peptides.

Methods are described for the design of amphipathic helical AMPs, to improve potency and/or increase selectivity with respect to host cells. One method is based on the statistical analysis of known helical AMPs to derive a sequence template and ranges of charge, hydrophobicity, and amphipathicity (hydrophobic moment) values that lead to broad-spectrum activity, but leaves optimization for selectivity to subsequent rounds of SAR determinations. A second method uses a small database of anuran AMPs with known potency (MIC values vs.

PGLa-H tandem-repeat peptides active against multidrug resistant clinical bacterial isolates.

Antimicrobial peptides (AMPs) are promising candidates for new antibiotic classes but often display an unacceptably high toxicity towards human cells. A naturally produced C-terminal fragment of PGLa, named PGLa-H, has been reported to have a very low haemolytic activity while maintaining a moderate antibacterial activity. A sequential tandem repeat of this fragment, diPGLa-H, was designed, as well as an analogue with a Val to Gly substitution at a key position.

Predicting the Minimal Inhibitory Concentration for Antimicrobial Peptides with Rana-Box Domain.

The global spreading of multidrug resistance has motivated the search for new antibiotic classes including different types of antimicrobial peptides (AMPs). Computational methods for predicting activity in terms of the minimal inhibitory concentration (MIC) of AMPs can facilitate "in silico" design and reduce the cost of synthesis and testing. We have used an original method for separating training and test data sets, both of which contain the sequences and measured MIC values of non-homologous anuran peptides having the Rana-box disulfide motif at their C-terminus.

Trichoplaxin - a new membrane-active antimicrobial peptide from placozoan cDNA.

A method based on the use of signal peptide sequences from antimicrobial peptide (AMP) precursors was used to mine a placozoa expressed sequence tag database and identified a potential antimicrobial peptide from Trichoplax adhaerens. This peptide, with predicted sequence FFGRLKSVWSAVKHGWKAAKSR is the first AMP from a placozoan species, and was named trichoplaxin. It was chemically synthesized and its structural properties, biological activities and membrane selectivity were investigated.

Selective antimicrobial activity and mode of action of adepantins, glycine-rich peptide antibiotics based on anuran antimicrobial peptide sequences.

A challenge when designing membrane-active peptide antibiotics with therapeutic potential is how to ensure a useful antibacterial activity whilst avoiding unacceptable cytotoxicity for host cells. Understanding their mode of interaction with membranes and the reasons underlying their ability to distinguish between bacterial and eukaryotic cytoplasmic cells is crucial for any rational attempt to improve this selectivity. We have approached this problem by analysing natural helical antimicrobial peptides of anuran origin, using a structure-activity database to determine an antimicrobial selectivity index (SI) relating the minimal inhibitory concentration against Escherichia coli to the haemolytic activity (SI=HC(50)/MIC).

Improving the selectivity of antimicrobial peptides from anuran skin.

Anuran skin is known to be a rich source of antimicrobial peptides although their therapeutic potential is often limited due to their toxicity against mammalian cells. The analysis of structure-activity relationships among anuran antimicrobial peptides provided the parameters to construct the "Mutator" tool for improving their selectivity for bacterial cells, by suggesting appropriate point substitutions. Double substitution analogues [K2, K16] of the Xenopus tropicalis peptide XT-7 and [I2, K19] of the Ascaphus truei peptide ascaphin-8 were predicted by this tool to have an increased 'therapeutic index' (TI = HC(50)/MIC for erythrocytes with respect to bacteria) > 80.

DADP: the database of anuran defense peptides.

Anuran tissues, and especially skin, are a rich source of bioactive peptides and their precursors. We here present a manually curated database of antimicrobial and other defense peptides with a total of 2571 entries, most of them in the precursor form with demarcated signal peptide (SP), acidic proregion(s) and bioactive moiety(s) corresponding to 1923 non-identical bioactive sequences. Search functions on the corresponding web server facilitate the extraction of six distinct SP classes.

Identification of antimicrobial peptides from teleosts and anurans in expressed sequence tag databases using conserved signal sequences.

The problem of multidrug resistance requires the efficient and accurate identification of new classes of antimicrobial agents. Endogenous antimicrobial peptides produced by most organisms are a promising source of such molecules. We have exploited the high conservation of signal sequences in teleost and anuran antimicrobial peptides to search cDNA (expressed sequence tag) databases for likely candidates.

Enzyme kinetics and the maximum entropy production principle.

A general proof is derived that entropy production can be maximized with respect to rate constants in any enzymatic transition. This result is used to test the assumption that biological evolution of enzyme is accompanied with an increase of entropy production in its internal transitions and that such increase can serve to quantify the progress of enzyme evolution. The state of maximum entropy production would correspond to fully evolved enzyme.

Knowledge-based computational methods for identifying or designing novel, non-homologous antimicrobial peptides.

We describe computational approaches for identifying promising lead candidates for the development of peptide antibiotics, in the context of quantitative structure-activity relationships (QSAR) studies for this type of molecule. A first approach deals with predicting the selectivity properties of generated antimicrobial peptide sequences in terms of measured therapeutic indices (TI) for known antimicrobial peptides (AMPs). Based on a training set of anuran AMPs, the concept of sequence moments was used to construct algorithms that could predict TIs for a second test set of natural AMPs and could also predict the effect of point mutations on TI values.

Bacterial chemotaxis and entropy production.

Entropy production is calculated for bacterial chemotaxis in the case of a migrating band of bacteria in a capillary tube. It is found that the speed of the migrating band is a decreasing function of the starting concentration of the metabolizable attractant. The experimentally found dependence of speed on the starting concentration of galactose, glucose and oxygen is fitted with power-law functions.

Computational design of highly selective antimicrobial peptides.

We have created a structure-selectivity database (AMPad) of frog-derived, helical antimicrobial peptides (AMPs), in which the selectivity was determined as a therapeutic index (TI), and then used the novel concept of sequence moments to study the lengthwise asymmetry of physicochemical peptide properties. We found that the cosine of the angle between two sequence moments obtained with different hydrophobicity scales, defined as the D-descriptor, identifies highly selective peptide antibiotics. We could then use this descriptor to predict TI changes after point mutations in known AMPs, and to aid the prediction of TI for de novo designed AMPs.

Kirchhoff's loop law and the maximum entropy production principle.

In contrast to the standard derivation of Kirchhoff's loop law, which invokes electric potential, we show, for the linear planar electric network in a stationary state at the fixed temperature, that loop law can be derived from the maximum entropy production principle. This means that the currents in network branches are distributed in such a way as to achieve the state of maximum entropy production.