Bulky Side Chains Research Articles

In situ continuous hydrogen-bonded engineering for intrinsically stretchable and healable high-mobility polymer semiconductors.

As a key component for wearable electronics, intrinsically stretchable and healable semiconducting polymers are scarce because carrier mobility is often reduced with increasing stretchability and self-healability. Here, we combine stepwise polymerization and thermal conversion to introduce in situ continuous hydrogen bonding sites in a polymer backbone without breaking the conjugation or introducing bulky softer side chains, benefiting the intrachain and interchain charge transport. We demonstrate that a regular sequence structure facilitated the formation of big nanofibers with a high degree of aggregation, providing the loose and porous thin film with simultaneously improved charge transport, stretchability, and self-healability. The mobility of damaged devices can be recovered to 81% after a healing treatment. Fully stretchable transistor based on the designed polymer exhibited a greatly enhanced mobility up to 1.08 square centimeters per volt per second under 100% strain, which is an unprecedented value and constitutes a major step for the development of intrinsically stretchable and healable semiconducting polymers.

Structural changes of Natronomonas pharaonis halorhodopsin in its late photocycle revealed by solid-state NMR spectroscopy

Natronomonas pharaonis halorhodopsin (NpHR) is a light-driven Cl− inward pump that is widely used as an optogenetic tool. Although NpHR is previously extensively studied, its Cl− uptake process is not well understood from the protein structure perspective, mainly because in crystalline lattice, it has been difficult to analyze the structural changes associated with the Cl− uptake process. In this study, we used solid-state NMR to analyze NpHR both in the Cl−-bound and -free states under near-physiological transmembrane condition. Chemical shift perturbation analysis suggested that while the structural change caused by the Cl− depletion is widespread over the NpHR molecule, residues in the extracellular (EC) part of helix D exhibited significant conformational changes that may be related to the Cl− uptake process. By combining photochemical analysis and dynamic nuclear polarization (DNP)-enhanced solid-state NMR measurement on NpHR point mutants for the suggested residues, we confirmed their importance in the Cl− uptake process. In particular, we found the mutation at Ala165 position, located at the trimer interface, to an amino acid with bulky sidechain (A165V) significantly perturbs the late photocycle and disrupts its trimeric assembly in the Cl−-free state as well as during the ion-pumping cycle under the photo-irradiated condition. This strongly suggested an outward movement of helix D at EC part, disrupting the trimer integrity. Together with the spectroscopic data and known NpHR crystal structures, we proposed a model that this helix movement is required for creating the Cl− entrance path on the extracellular surface of the protein and is crucial to the Cl− uptake process.

Exploration of Tertiary Structure in Sequence-Defined Polymers Using Molecular Dynamics Simulations.

Peptoids are a class of sequence-defined biomimetic polymers with peptide-like backbones and side chains located on backbone nitrogens rather than alpha carbons. These materials demonstrate a strong ability for precise control of single-chain structure, multiunit self-assembly, and macromolecular assembly through careful tuning of sequence due to the diversity of available side chains, although the driving forces behind these assemblies are often not understood. Prior experimental work has shown that linked 15mer peptoids can mimic the protein helical hairpin structure by leveraging the chirality-inducing nature of bulky side chains and hydrophobicity, but there are still gaps in our understanding of the relationship between sequence, stability, and particular secondary or tertiary structure. We present a molecular dynamics (MD) study on the folding behavior of these polymers into hairpins, discussing the differences in structure from sequences with various characteristics in water and acetonitrile, and then compare the handedness preference of common helical motifs between solvents.

Direct Enantioselective α-C-H Conjugate Addition of Propargylamines to α,β-Unsaturated Ketones via Carbonyl Catalysis.

Direct asymmetric α-C-H conjugate addition of propargylamines to α,β-unsaturated ketones remains a great challenge due to the low α-amino C-H acidity of propargylamines and the nucleophilic interference of the NH2 group. Utilizing a new type of pyridoxals featuring a benzene-pyridine biaryl skeleton and a bulky amide side chain as carbonyl catalyst, we have accomplished direct asymmetric α-C-H conjugate addition of NH2-unprotected propargylamines to α,β-unsaturated ketones. The adducts undergo subsequent in situ intramolecular cyclization, delivering a wide range of chiral polysubstituted 1-pyrrolines in high yields (up to 92%) with excellent diastereo- and enatioelectivities (up to >20:1 dr and 99% ee). This work has demonstrated a straightforward approach to access pharmaceutically important chiral 1-pyrrolines, and it has also provided an impressive instance of direct asymmetric functionalization of inert C-H bonds enabled by biomimetic organocatalysts.

High electrical conductivity induced by charge transfer interactions in naphthalenediimide derivatives

Various studies have shown the influence of aliphatic, aromatic and bulky side chains on the optical, electrical conductivity and charge transport properties of naphthalenediimide (NDI) derivatives. The morphology, structural arrangement and the aggregation behaviour of these derivatives play an important role in influencing the charge transfer interactions between the donor and acceptor. These properties influence the electrical conductivity of the derivatives due to presence of charge transfer interactions. The present work focuses on the structure property relationship of the four NDI derivatives (SB-NDI) synthesized by imidization of dianhydride precursor with primary amine terminated Schiff bases (SB). The SB-NDI derivatives bear terminal phenyl ring attached to NDI through unsaturated or double unsaturated linkers bearing different electron withdrawing and donating groups. Among these, SB-NDI-2 derivative bearing –NO2 group in trans position at the terminal phenyl ring shows lowest –ΔGoET(CS) which allows favorable intramolecular charge separation. The Scanning electron microscopy shows ribbon like morphology for SB-NDI-2. The micron sized ribbons provide better charge transport and a conductivity of ∼1 Sm−1 at the room temperature without any additives. The special structure of SB-NDI provides charge transport properties allowing wide applications in the field of optoelectronics.

Probing the interaction between the metallo-β-lactamase SMB-1 and ampicillin by multispectral approaches combined with molecular dynamics.

Metallo-β-lactamases (MβLs) hydrolyze and inactivate β-lactam antibiotics, are a pivotal mechanism conferring resistance against bacterial infections. SMB-1, a novel B3 subclass of MβLs from Serratia marcescens could deactivate almost all β-lactam antibiotics including ampicillin (AMP), which has posed a serious threat to public health. To illuminate the mechanism of recognition and interaction between SMB-1 and AMP, various fluorescence spectroscopy techniques and molecular dynamics simulation were employed. The results of quenching spectroscopy unraveled that AMP could make SMB-1 fluorescence quenching that mechanism was the static quenching; the synchronous and three-dimensional fluorescence spectra validated that the microenvironment and conformation of SMB-1 were altered after interaction with AMP. The molecular dynamics results demonstrated that the whole AMP enters the binding pocket of SMB-1, even though with a relatively bulky R1 side chain. Loop1 and loop2 in SMB-1 undergo significant fluctuations, and α2 (71-73) and local α5 (186-188) were turned into random coils, promoting zinc ion exposure consistent with circular dichroism spectroscopy results. The binding between them was driven by a combination of enthalpy and entropy changes, which was dominated by electrostatic force in agreement with the fluorescence observations. The present study brings structural insights and solid foundations for the design of new substrates for β-lactamases and the development of effective antibiotics that are resistant to superbugs.

Air processed, high open‐circuit voltage indoor organic photovoltaic cells based on side chain modified N‐annulated perylene diimides

AbstractTo achieve high‐performance indoor organic photovoltaics (OPVs), it is important to match the photoactive layer optical absorption with the light‐source emission. This can be accomplished by developing organic photoactive materials that can efficiently absorb visible light and thus minimize energy losses. While indoor OPVs have achieved efficiencies above 33% under low light intensities, the power output is limited by low open circuit voltages (VOC), often well below 1 V. In this study, we present a series of visible‐light absorbing (energy gap >1.90 eV) non‐fullerene acceptors (NFAs) based on perylene diimide dimers, which have been systematically modified with side chains of varying polarity and steric bulk (trimethyl benzyl, ethyl adamantane, trialkoxyl phenyl, and oligo ethylene glycol). Our results show that the incorporation of sterically bulky side chains such as ethyl adamantane and trimethyl benzyl, blended with the common widegap polymer PTQ10, provides photoactive layers with absorption greater than 2.0 eV, and consequently, VOCs higher than 1.2 V are achieved under AM 1.5 G illumination. Importantly, we found that the NFA with ethyl adamantane based side chains (tPDI2N‐ethyl adamantane, compound 4) exhibited the best performance, with minimized energy loss. As a result, devices using PTQ10:tPDI2N‐ethyl adamantane photoactive layers demonstrated excellent indoor efficiencies of over 16% and 18 μW cm−2 power output under a 2700 K LED lamp at 300 lux, and showed better repeatability compared to other systems. The PTQ10:tPDI2N‐ethyl adamantane based devices maintained a high VOC (>1.0 V) across a wide range of indoor lighting conditions, including 2700 K and 6500 K LED lamps. Overall, this work provides a sidechain engineering method to create NFAs for efficient indoor OPV devices.

Steric hindrance induced low exciton binding energy enables low‐driving‐force organic solar cells

AbstractExciton binding energy (Eb) has been regarded as a critical parameter in charge separation during photovoltaic conversion. Minimizing the Eb of the photovoltaic materials can facilitate the exciton dissociation in low‐driving force organic solar cells (OSCs) and thus improve the power conversion efficiency (PCE); nevertheless, diminishing the Eb with deliberate design principles remains a significant challenge. Herein, bulky side chain as steric hindrance structure was inserted into Y‐series acceptors to minimize the Eb by modulating the intra‐ and intermolecular interaction. Theoretical and experimental results indicate that steric hindrance‐induced optimal intra‐ and intermolecular interaction can enhance molecular polarizability, promote electronic orbital overlap between molecules, and facilitate delocalized charge transfer pathways, thereby resulting in a low Eb. The conspicuously reduced Eb obtained in Y‐ChC5 with pinpoint steric hindrance modulation can minimize the detrimental effects on exciton dissociation in low‐driving‐force OSCs, achieving a remarkable PCE of 19.1% with over 95% internal quantum efficiency. Our study provides a new molecular design rationale to reduce the Eb.

Engineering polyamide materials: s-triazine framework with specialized bulky side chains for advanced applications

The focus of this study is on the synthesis of organic fluorescent and thermally stable polyamides using an s-triazine frame. Coumarin and n-phenyl anthranilic acid have been utilized as bulky pendent groups in the synthesis of the monomer, resulting in polyamides with two groups that enhance stability and fluorescence. The synthesized polyamides have been characterized using a variety of techniques. The thermal stability of the polyamides has been studied using thermogravimetric analysis. These polyamides offer appealing features such as fluorescence and enhanced thermal stability, making them significant for a wide range of applications, including biosensors, clean energy technologies, and explosive sensing.

Abstract 1021: Bulky Hydrophobic Side Chains In The β1-sandwich Of Microsomal Triglyceride Transfer Protein Are Critical For The Transfer Of Both Triglycerides And Phospholipids

Hyperlipidemia predispose individuals to cardio-metabolic diseases, the most common cause of global mortality. Microsomal triglyceride transfer protein (MTP) transfers multiple lipids and is essential for the assembly of apoB-containing lipoproteins. MTP inhibition lowers plasma lipids but causes lipid retention in the liver and intestine. Previous studies suggested two lipid transfer domains in MTP and that specific inhibition of triglycerides (TG) and not phospholipids (PL) transfer can lower plasma lipids without significant tissue lipid accumulation. However, how MTP transfers different lipids and the domains involved in these activities are unknown. Here, we tested a hypothesis that two different β-sandwich domains in MTP transfer TG and PL. Mutagenesis of charged amino acids in β2-sandwich had no effect on PL transfer activity indicating that they are not critical. In contrast, amino acids with bulky hydrophobic side chains in β1-sandwich were critical for both TG and PL transfer activities. Substitutions of these residues with smaller hydrophobic side chains or positive charges reduced, while negatively charged side chains severely attenuated MTP lipid transfer activities. These studies point to a common lipid transfer domain for TG and PL in MTP that is enriched with bulky hydrophobic amino acids. Furthermore, we observed a strong correlation in different MTP mutants with respect to loss of both the lipid transfer activities, again implicating a common binding site for TG and PL in MTP. We propose that targeting of areas other than the identified common lipid transfer domain might reduce plasma lipids without causing cellular lipid retention.

Recent Advances in the Field of Amino Acid-Conjugated Aminoferrocenes-A Personal Perspective.

The development of turn-based inhibitors of protein-protein interactions has attracted considerable attention in medicinal chemistry. Our group has synthesized a series of peptides derived from an amino-functionalized ferrocene to investigate their potential to mimic protein turn structures. Detailed DFT and spectroscopic studies (IR, NMR, CD) have shown that, for peptides, the backbone chirality and bulkiness of the amino acid side chains determine the hydrogen-bond pattern, allowing tuning of the size of the preferred hydrogen-bonded ring in turn-folded structures. However, their biological potential is more dependent on their lipophilicity. In addition, our pioneering work on the chiroptical properties of aminoferrocene-containing peptides enables the correlation of their geometry with the sign of the CD signal in the absorption region of the ferrocene chromophore. These studies have opened up the possibility of using aminoferrocene and its derivatives as chirooptical probes for the determination of various chirality elements, such as the central chirality of amino acids and the helicity of peptide sequences.

Bulky hydrophobic side chains in the β1-sandwich of microsomal triglyceride transfer protein are critical for the transfer of both triglycerides and phospholipids

Hyperlipidemia predisposes individuals to cardiometabolic diseases, the most common cause of global mortality. Microsomal triglyceride transfer protein (MTP) transfers multiple lipids and is essential for the assembly of apolipoprotein B-containing lipoproteins. MTP inhibition lowers plasma lipids but causes lipid retention in the liver and intestine. Previous studies suggested two lipid transfer domains in MTP and that specific inhibition of triglyceride (TG) and not phospholipid (PL) transfer can lower plasma lipids without significant tissue lipid accumulation. However, how MTP transfers different lipids and the domains involved in these activities are unknown. Here, we tested a hypothesis that two different β-sandwich domains in MTP transfer TG and PL. Mutagenesis of charged amino acids in β2-sandwich had no effect on PL transfer activity indicating that they are not critical. In contrast, amino acids with bulky hydrophobic side chains in β1-sandwich were critical for both TG and PL transfer activities. Substitutions of these residues with smaller hydrophobic side chains or positive charges reduced, whereas negatively charged side chains severely attenuated MTP lipid transfer activities. These studies point to a common lipid transfer domain for TG and PL in MTP that is enriched with bulky hydrophobic amino acids. Furthermore, we observed a strong correlation in different MTP mutants with respect to loss of both the lipid transfer activities, again implicating a common binding site for TG and PL in MTP. We propose that targeting of areas other than the identified common lipid transfer domain might reduce plasma lipids without causing cellular lipid retention.

The Role of Key Amino Acids of the Human Fe(II)/2OG-Dependent Dioxygenase ALKBH3 in Structural Dynamics and Repair Activity toward Methylated DNA.

Non-heme dioxygenases of the AlkB family hold a unique position among enzymes that repair alkyl lesions in nucleic acids. These enzymes activate the Fe(II) ion and molecular oxygen through the coupled decarboxylation of the 2-oxoglutarate co-substrate to subsequently oxidize the substrate. ALKBH3 is a human homolog of E. coli AlkB, which displays a specific activity toward N1-methyladenine and N3-methylcytosine bases in single-stranded DNA. Due to the lack of a DNA-bound structure of ALKBH3, the basis of its substrate specificity and structure-function relationships requires further exploration. Here we have combined biochemical and biophysical approaches with site-directed mutational analysis to elucidate the role of key amino acids in maintaining the secondary structure and catalytic activity of ALKBH3. Using stopped-flow fluorescence spectroscopy we have shown that conformational dynamics play a crucial role in the catalytic repair process catalyzed by ALKBH3. A transient kinetic mechanism, which comprises the steps of the specific substrate binding, eversion, and anchoring within the DNA-binding cleft, has been described quantitatively by rate and equilibrium constants. Through CD spectroscopy, we demonstrated that replacing side chains of Tyr143, Leu177, and His191 with alanine results in significant alterations in the secondary structure content of ALKBH3 and decreases the stability of mutant proteins. The bulky side chain of Tyr143 is critical for binding the methylated base and stabilizing its flipped-out conformation, while its hydroxyl group is likely involved in facilitating the product release. The removal of the Leu177 and His191 side chains substantially affects the secondary structure content and conformational flexibility, leading to the complete inactivation of the protein. The mutants lacking enzymatic activity exhibit a marked decrease in antiparallel β-strands, offset by an increase in the helical component.

The SAMPL9 host-guest blind challenge: an overview of binding free energy predictive accuracy.

We report the results of the SAMPL9 host-guest blind challenge for predicting binding free energies. The challenge focused on macrocycles from pillar[n]-arene and cyclodextrin host families, including WP6, and bCD and HbCD. A variety of methods were used by participants to submit binding free energy predictions. A machine learning approach based on molecular descriptors achieved the highest accuracy (RMSE of 2.04 kcal mol-1) among the ranked methods in the WP6 dataset. Interestingly, predictions for WP6 obtained via docking tended to outperform all methods (RMSE of 1.70 kcal mol-1), most of which are MD based and computationally more expensive. In general, methods applying force fields achieved better correlation with experiments for WP6 opposed to the machine learning and docking models. In the cyclodextrin-phenothiazine challenge, the ATM approach emerged as the top performing method with RMSE less than 1.86 kcal mol-1. Correlation metrics of ranked methods in this dataset were relatively poor compared to WP6. We also highlight several lessons learned to guide future work and help improve studies on the systems discussed. For example, WP6 may be present in other microstates other than its -12 state in the presence of certain guests. Machine learning approaches can be used to fine tune or help train force fields for certain chemistry (i.e. WP6-G4). Certain phenothiazines occupy distinct primary and secondary orientations, some of which were considered individually for accurate binding free energies. The accuracy of predictions from certain methods while starting from a single binding pose/orientation demonstrates the sensitivity of calculated binding free energies to the orientation, and in some cases the likely dominant orientation for the system. Computational and experimental results suggest that guest phenothiazine core traverses both the secondary and primary faces of the cyclodextrin hosts, a bulky cationic side chain will primarily occupy the primary face, and the phenothiazine core substituent resides at the larger secondary face.

Molecular modeling and phylogenetic analyses highlight the role of amino acid 347 of the N1 subtype neuraminidase in influenza virus host range and interspecies adaptation.

The N1 neuraminidases (NAs) of avian and pandemic human influenza viruses contain tyrosine and asparagine, respectively, at position 347 on the rim of the catalytic site; the biological significance of this difference is not clear. Here, we used molecular dynamics simulation to model the effects of amino acid 347 on N1 NA interactions with sialyllacto-N-tetraoses 6'SLN-LC and 3'SLN-LC, which represent NA substrates in humans and birds, respectively. Our analysis predicted that Y347 plays an important role in the NA preference for the avian-type substrates. The Y347N substitution facilitates hydrolysis of human-type substrates by resolving steric conflicts of the Neu5Ac2-6Gal moiety with the bulky side chain of Y347, decreasing the free energy of substrate binding, and increasing the solvation of the Neu5Ac2-6Gal bond. Y347 was conserved in all N1 NA sequences of avian influenza viruses in the GISAID EpiFlu database with two exceptions. First, the Y347F substitution was present in the NA of a specific H6N1 poultry virus lineage and was associated with the substitutions G228S and/or E190V/L in the receptor-binding site (RBS) of the hemagglutinin (HA). Second, the highly pathogenic avian H5N1 viruses of the Gs/Gd lineage contained sporadic variants with the NA substitutions Y347H/D, which were frequently associated with substitutions in the HA RBS. The Y347N substitution occurred following the introductions of avian precursors into humans and pigs with N/D347 conserved during virus circulation in these hosts. Comparative evolutionary analysis of site 347 revealed episodic positive selection across the entire tree and negative selection within most host-specific groups of viruses, suggesting that substitutions at NA position 347 occurred during host switches and remained under pervasive purifying selection thereafter. Our results elucidate the role of amino acid 347 in NA recognition of sialoglycan substrates and emphasize the significance of substitutions at position 347 as a marker of host range and adaptive evolution of influenza viruses.

A Stereoselective Entry to Enantiopure (S)-2-Amino-2-methyl-5-arylpent-4-ynoic Acids and Evaluation of Their Inhibitory Activity against Bacterial Collagenase G

Nowadays, amino acids (AAs) and peptides with bulky side chains hold significant interest for organic synthesis and the modern pharma industry. Non-proteinogenic (or unnatural) AAs are key building blocks used for obtaining pharmaceutically relevant peptides and for the development of chiral molecular catalysts, and they are extensively used in the total synthesis of complex natural compounds. Thus, an elaboration of cost-effective methods for the preparation of novel unnatural AAs to increase their structural diversity is highly desirable. In this context, herein, we present an asymmetric metal-templated synthesis of a number of enantiomerically pure (S)-2-amino-2-methyl-5-arylpent-4-ynoic acids starting from commercially available reagents and Belokon’s chiral auxiliary (S)-BPB, namely (S)-2-(N-benzylprolyl)aminobenzophenone. The construction of a chiral Ni(II) complex from alanine (Ala) and the subsequent propargylation, arylation by the Sonogashira cross-coupling reaction using various aryl halides, and, finally, an acidic decomposition of the obtained complexes deliver to the target complex α,α-disubstituted AAs featuring a triple bond in a side chain. Next, the Fmoc-protected α-AAs and dipeptide were synthesized. Finally, we examined the obtained α-AAs and peptide as collagenase inhibitors.

Microstructural Model of Indacenodithiophene-co-benzothiadiazole Polymer: π-Crossing Interactions and Their Potential Impact on Charge Transport.

Morphological and electronic properties of indacenodithiophene-co-benzothiadiazole (IDTBT) copolymer with varying molecular weights are calculated through combined molecular dynamics (MD) and quantum chemical (QC) methods. Our study focuses on the polymer chain arrangements, interchain connectivity pathways, and interplay between morphological and electronic structure properties of IDTBT. Our models, which are verified against GIWAXS measurements, show a considerable number of BT-BT π-π interactions with a (preferential) perpendicular local orientation of polymer chains due to the steric hindrance of bulky side chains around IDT. Although our models predict a noncrystalline structure for IDTBT, the BT-BT (interchain) crossing points show a considerable degree of short-range order in spatial arrangement which most likely result in a mesh-like structure for the polymer and provide efficient pathways for interchain charge transport.

In Silico Design and Analysis of Plastic-Binding Peptides.

Peptides that bind to inorganic materials can be used to functionalize surfaces, control crystallization, or assist in interfacial self-assembly. In the past, inorganic-binding peptides have been found predominantly through peptide library screening. While this method has successfully identified peptides that bind to a variety of materials, an alternative design approach that can intelligently search for peptides and provide physical insight for peptide affinity would be desirable. In this work, we develop a computational, physics-based approach to design inorganic-binding peptides, focusing on peptides that bind to the common plastics polyethylene, polypropylene, polystyrene, and poly(ethylene terephthalate). The PepBD algorithm, a Monte Carlo method that samples peptide sequence and conformational space, was modified to include simulated annealing, relax hydration constraints, and an ensemble of conformations to initiate design. These modifications led to the discovery of peptides with significantly better scores compared to those obtained using the original PepBD. PepBD scores were found to improve with increasing van der Waals interactions, although strengthening the intermolecular van der Waals interactions comes at the cost of introducing unfavorable electrostatic interactions. The best designs are enriched in amino acids with bulky side chains and possess hydrophobic and hydrophilic patches whose location depends on the adsorbed conformation. Future work will evaluate the top peptide designs in molecular dynamics simulations and experiment, enabling their application in microplastic pollution remediation and plastic-based biosensors.

Laser Interfaced Mass Spectrometry of the Sunscreen Molecule Octocrylene Demonstrates that Protonation Does Not Impact Photostability

AbstractOctocrylene (OCR) is a widely used organic sunscreen molecules, and is a dominant component of many sunscreen formulations. Here, we perform the first measurements on the protonated form of OCR, i. e. [OCR+H]+, to probe whether protonation affects the molecule's photostability. The novel photochemical technique of UV laser‐interfaced mass spectrometry is employed from 400–216 nm, revealing that the electronic absorption spectrum of OCR across the S1 and S2 states red shift by 40 nm upon protonation. Our measurements reveal that [OCR+H]+ predominantly undergoes photofragmentation into the m/z 250 and 232 ionic products, associated with loss of its bulky alkyl side chain, and subsequent loss of water, respectively. We compare the photochemical fragmentation results with higher‐energy collisional dissociation results to investigate the nature of the photodynamics that occur following UV absorption. The excited state decay pathways over the S1 and S2 excited states of [OCR+H]+ are associated with statistical fragmentation in line with dominant ultrafast decay. This behaviour mirrors that of neutral OCR, demonstrating that protonation does not affect the ultrafast decay pathways of this sunscreen molecule. We discuss our results in the context of the known breakdown of OCR into benzophenone, identifying a potential photoactivated pathway to benzophenone formation in solution.

Categorization of hotspots into three types – weak, moderate and strong to distinguish protein–protein versus protein–peptide interactions

Protein–protein and protein–peptide interactions (PPI and PPepI) belong to a similar category of interactions, yet seemingly subtle differences exist among them. To characterize differences between protein–protein (PP) and protein–peptide (PPep) interactions, we have focussed on two important classes of residues-hotspot and anchor residues. Using implicit solvation-based free energy calculations, a very large-scale alanine scanning has been performed on benchmark datasets, consisting of over 5700 interface residues. The differences in the two categories are more pronounced, if the data were divided into three distinct types, namely – weak hotspots (having binding free energy loss upon Ala mutation, ΔΔG, ∼2–10 kcal/mol), moderate hotspots (ΔΔG, ∼10–20 kcal/mol) and strong hotspots (ΔΔG ≥ ∼20 kcal/mol). The analysis suggests that for PPI, weak hotspots are predominantly populated by polar and hydrophobic residues. The distribution shifts towards charged and polar residues for moderate hotspot and charged residues (principally Arg) are overwhelmingly present in the strong hotspot. On the other hand, in the PPepI dataset, the distribution shifts from predominantly hydrophobic and polar (in the weak type) to almost similar preference for polar, hydrophobic and charged residues (in moderate type) and finally the charged residue (Arg) and Trp are mostly occupied in the strong type. The preferred anchor residues in both categories are Arg, Tyr and Leu, possessing bulky side chain and which also strike a delicate balance between side chain flexibility and rigidity. The present knowledge should aid in effective design of biologics, by augmentation or disruption of PPIs with peptides or peptidomimetics. Communicated by Ramaswamy H. Sarma