Computational methods to estimate passive membrane permeability coefficients of organic molecules, including peptides, would be valuable in understanding various biological processes associated with molecular transport across cell membranes and in reducing the time required for screening developability properties of new drug candidates. This study explores the suitability of fragment-based linear free energy relationships (LFERs) to predict lipid bilayer permeability coefficients and decadiene/water partition coefficients of a set of 47 model permeants. The inclusion of mono-, di-, and tripeptides comprised of glycine, alanine, and sarcosine residues in the database presented added challenges due to the apparent lack of independence of the contribution of the backbone amide residue in peptides to the free energy of transfer (Delta(Delta G degrees ) -CONH-) from water to organic solvents or to the bilayer barrier domain. In order to elucidate the impact of neighboring group effects on Delta(Delta G degrees ) -CONH-, a series of RGZ glycine (G)-containing peptides having an additional -NHCH 2CO- residue compared to their RZ counterparts were synthesized, where R = acetyl (Ac-), 4-carboxymethylphenyl acetyl (CMPA-), or 4-methylphenyl acetyl (MPA-), and Z = -OH, -OMe, -NHMe, or -NMe 2. While variations in R had no significant impact on Delta(Delta G degrees ) -Gly-, significant effects of neighboring ( i + 1) Z substituents at the C-terminus were revealed both in studies of the relative transport of RGZ/RZ compound pairs across DOPC bilayers and partitioning between water and 1,9-decadiene (a bulk solvent with a similar chemical selectivity to the barrier domain of DOPC/eggPC bilayers). The proximity effects decline when the bulk solvent used in partitioning studies is 1-octanol, suggesting a possible role for intramolecular hydrogen bonding in the observed nonadditivity of Delta(Delta G degrees ) -CONH-. A new LFER for predicting decadiene/water partition coefficients was developed by including the contributions of polar fragments, total nonpolar surface area of nonpolar fragments, and correction factors to account for the effects of i + 1 substituents in peptides on the group contribution of the peptide backbone amide bond to the free energy of transfer. This LFER could be used to predict lipid bilayer permeability coefficients by including an additional term to account for the added influence of molecular size on bilayer permeability.

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Substrate leveling is an essential but neglected instrumental technique of scanning electrochemical microscopy (SECM). In this technical note, we provide an effective substrate leveling method based on the current feedback mode of SECM. By using an air-bearing rotary stage as the supporter of an electrolytic cell, the current feedback presents a periodic waveform signal, which can be used to characterize the levelness of the substrate. Tuning the adjusting screws of the tilt stage, substrate leveling can be completed in minutes by observing the decreased current amplitude. The obtained high-quality SECM feedback curves and images prove that this leveling technique is valuable in not only SECM studies but also electrochemical machining.

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The confined etchant layertechnique (CELT) has been proved an effective electrochemical microfabrication method since its first publication at Faraday Discussions in 1992. Recently, we have developed CELT as an electrochemical mechanical micromachining (ECMM) method by replacing the cutting tool used in conventional mechanical machining with an electrode, which can perform lathing, planing and polishing. Through the coupling between the electrochemically induced chemical etching processes and mechanical motion, ECMM can also obtain a regular surface in one step. Taking advantage of CELT, machining tolerance and surface roughness can reach micro- or nano-meter scale.

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Scanning electrochemical microscopy (SECM) is one of the most important instrumental methods of modern electrochemistry due to its high spatial and temporal resolution. We introduced SECM into nanomachining by feeding the electrochemical modulations of the tip electrode back to the positioning system, and we demonstrated that SECM is a versatile nanomachining technique on semiconductor wafers using electrochemically induced chemical etching. The removal profile was correlated to the applied tip current when the tip was held stationary and when it was moving slowly (<20 μm s−1), and it followed Faraday's law. Both regular and irregular nanopatterns were translated into a spatially distributed current by the homemade digitally controlled SECM instrument. The desired nanopatterns were “sculpted” directly on a semiconductor wafer by SECM direct‐writing mode. The machining accuracy was controlled to the sub‐micrometer and even nanometer scales. This advance is expected to play an important role in electrochemical nanomachining for 3D micro/nanostructures in the semiconductor industry.

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