Side Chain-side Chain Interactions Research Articles

Exploring conformations of comb-like polymers with varying grafting density in dilute solutions.

Comb-like polymers have shown potential as advanced materials for a diverse palette of applications due to the tunability of their polymer architecture. To date, however, it still remains a challenge to understand how the conformational properties of these polymers arise from the interplay of their architectural parameters. In this work, extensive simulations were performed using dissipative particle dynamics to investigate the effect of grafting density, backbone length, and sidechain length on the conformations of comb-like polymers immersed in a good solvent. To quantify the effect of these architectural parameters on polymer conformations, we computed the asphericity, radius of gyration, and backbone and sidechain end-to-end distances. Bond-bond correlation functions and effective Kuhn lengths were computed to quantify the topological stiffness induced by sidechain-sidechain interactions. Simulation results reveal that the effective Kuhn length increases as grafting density and sidechain length increase, in agreement with previous experimental and theoretical studies. This increase in stiffness results in comb-like polymers adopting extended conformations as grafting density and sidechain length increase. Simulation results regarding the radius of gyration of comb-like polymers as a function of grafting density are compared with scaling theory predictions based on a free energy proposed by Morozova and Lodge [ACS Macro Lett. 6, 1274-1279 (2017)] and scaling arguments by Tang et al. [Macromolecules 55, 8668-8675 (2022)].

Binary and ternary complexes of FLNa-Ig21 with cytosolic tails of αMß2 integrin reveal dual role of filamin mediated regulation

BackgroundCytoskeletal protein filamin A is critical for the outside-in signaling of integrins. Although molecular mechanisms of filamin-integrin interactions are not fully understood. Mostly, the membrane distal (MD) part of the cytosolic tail (CT) of β subunit of integrin is known to interact with filamin A domain 21 (FLNa-Ig2). However, binary and ternary complexes of full-length CTs of leucocyte specific ß2 integrins with FLNa-Ig21 are yet to be elucidated. MethodsBinding interactions of the CTs of integrin αMß2 with FLNa-Ig21 are extensively investigated by NMR, ITC, cell-based functional assays and computational docking. ResultsThe αM CT demonstrates interactions with FLNa-Ig21 forming a binary complex. Filamin/αM interface is mediated by sidechain-sidechain interactions among non-polar and aromatic residues involving MP helix of αM and the canonical CD face of FLNa-Ig21. Functional assays delineated an interfacial residue Y1137 of αM CT is critical for in-cell binding to FLNa-Ig2. In addition, full-length ß2 CT occupies two distinct binding sites in complex with FLNa-Ig21. A ternary complex of FLNa-Ig21 with CTs has been characterized. In the ternary complex, αM CT moves away to a distal site of FLNa-Ig21 with fewer interactions. ConclusionOur findings demonstrate a plausible dual role of filamin in integrin regulation. The molecular interactions of the ternary complex are critical for the resting state of integrins whereas stable FLNa-Ig21/αM CT binary complex perhaps be required for the activated state. General significanceFilamin binding to both α and β CTs of other integrins could be essential in regulating bidirectional signaling mechanisms.

Structural Assessment of Agonist Efficacy in the μ-Opioid Receptor: Morphine and Fentanyl Elicit Different Activation Patterns.

Over the past two decades, the opioid epidemic in the United States and Canada has evidenced the need for a better understanding of the molecular mechanisms of medications used to fight pain. Morphine and fentanyl are widely used in opiate-mediated analgesia for the treatment of chronic pain. These compounds target the μ-opioid receptor (MOR), a class A G protein-coupled receptor (GPCR). In light of described higher efficacy of fentanyl with respect to morphine, we have performed independent μs-length unbiased molecular dynamics (MD) simulations of MOR complexes with each of these ligands, including the MOR antagonist naltrexone as a negative control. Consequently, MD simulations totaling 58 μs have been conducted to elucidate at the atomic level ligand-specific receptor activity and signal transmission in the MOR. In particular, we have identified stable binding poses of morphine and fentanyl, which interact differently with the MOR. Different ligand-receptor interaction landscapes directly induce sidechain conformational changes of orthosteric pocket residues: Asp1493.32, Tyr1503.33, Gln1262.60, and Lys2355.39. The induced conformations determine Asp1493.32-Tyr3287.43 sidechain-sidechain interactions and Trp2956.48-Ala2425.46 sidechain-backbone H-bond formations, as well as Met1533.36 conformational changes. In addition to differences in ligand binding, different intracellular receptor conformational changes are observed as morphine preferentially activates transmembrane (TM) helices: TM3 and TM5, while fentanyl preferentially activates TM6 and TM7. As conformational changes in TM6 and TM7 are widely described as being the most crucial aspect in GPCR activation, this may contribute to the greater efficacy of fentanyl over morphine. These computationally observed functional differences between fentanyl and morphine may provide new avenues for the design of safer but not weaker opioid drugs because it is desirable to increase the safety of medicines without sacrificing their efficacy.

Computational and experimental studies on the influence of theTrp-cage inter-residue interactions and other external factors on its structural and folding stability

<p indent=0mm>The major driving force of protein folding depends on their inter-residue interactions, especially for sidechain-sidechain interactions. The Trp-cage is a fast-folding mini-protein, which has already been acknowledged as an ideal model for tackling complicated folding-related problems of proteins. Although this protein model is merely composed of 20 amino acid residues, it exhibits an extremely complex interaction network between residues with different types of sidechain orientation. Because current force fields exhibit different degrees of accuracy inadequacies in the descriptions of atomic interactions, it remains a matter of debate at what stage of folding the helix, hydrophobic cluster and salt-bridge is being conclusively formed in its possible folding mechanisms. The structures and mutations of all the Trp-cage system reported since 2002 are summarized in this paper, and its two typical structures (TC5b and TC10b) are taken as examples to summarize the composition and types of their inter-residue interactions as well as the sidechain features and orientations. Meanwhile, the recent computational and experimental studies of several possible folding mechanisms are also generalized and discussed, and their relationships with simulation temperature and force field as well as the switching from one folding pathway to the other are also discussed in detail. Finally, the effects of numerous factors on structural stability and folding dynamics have been elaborately discussed, including different types of inter-residue interactions (such as salt-bridge, hydrophobic and hydrogen-bonding interactions) and environmental factors (such as temperature, pressure, pH and other potential factors). We also propose that the clarification of the above factors and their synergistic effects are beneficial not only to reveal the driving force of protein stabilization and rapid formation, but also to provide theoretical guidance for further structural regulation and optimal design.

Structural insights into the interaction of botulinum neurotoxin a with its neuronal receptor SV2C

A dual-receptor interaction with a polysialoganglioside and synaptic vesicle glycoprotein 2 (SV2) is required for botulinum neurotoxin A (BoNT) toxicity. Here, we review what is currently known about the BoNT/A-SV2 interaction based on structural studies. Currently, five crystal structures of the receptor–binding domain (Hc) of BoNT subtypes A1 and A2 complexed to the large luminal domain (LD4) of SV2C have been determined. On the basis of the available structures, we will discuss the importance of protein-protein and protein-carbohydrate interactions for BoNT/A toxicity as well as the high plasticity of BoNT/A for receptor recognition by tolerating a variety of side-chain interactions at the interface. A plausible explanation how receptor-binding specificity of BoNT/A may be achieved without an extensive and conserved side chain-side chain interaction network will be provided.

Effects of PHB and SFC charge models on the side chain-side chain interactions in the simulation of β-hairpins

In view of the recent development of polarizable force fields namely polarizable hydrogen bond (PHB) and semi-fluctuating charge (SFC) developed by Zhang’s group, we would like to explore the effects of these two models on side chain-side chain interactions through the simulation of two β-hairpins. The results show that the PHB model strengthens but the SFC model weakens side chain-side chain interactions in our studies. Through this study, we aim to have a more comprehensive understanding of these two models which only focus on the charge updating of backbone atoms.

Interaction Enthalpy of Side Chain and Backbone Amides in Polyglutamine Solution Monomers and Fibrils.

We determined an empirical correlation that relates the amide I vibrational band frequencies of the glutamine (Q) side chain to the strength of hydrogen bonding, van der Waals, and Lewis acid-base interactions of its primary amide carbonyl. We used this correlation to determine the Q side chain carbonyl interaction enthalpy (Δ Hint) in monomeric and amyloid-like fibril conformations of D2Q10K2 (Q10). We independently verified these Δ Hint values through molecular dynamics simulations that showed excellent agreement with experiments. We found that side chain-side chain and side chain-peptide backbone interactions in fibrils and monomers are more enthalpically favorable than are Q side chain-water interactions. Q10 fibrils also showed a more favorable Δ Hint for side chain-side chain interactions compared to backbone-backbone interactions. This work experimentally demonstrates that interamide side chain interactions are important in the formation and stabilization of polyQ fibrils.

Protein folding, misfolding and aggregation: The importance of two-electron stabilizing interactions.

Proteins associated with neurodegenerative diseases are highly pleiomorphic and may adopt an all-α-helical fold in one environment, assemble into all-β-sheet or collapse into a coil in another, and rapidly polymerize in yet another one via divergent aggregation pathways that yield broad diversity of aggregates’ morphology. A thorough understanding of this behaviour may be necessary to develop a treatment for Alzheimer’s and related disorders. Unfortunately, our present comprehension of folding and misfolding is limited for want of a physicochemical theory of protein secondary and tertiary structure. Here we demonstrate that electronic configuration and hyperconjugation of the peptide amide bonds ought to be taken into account to advance such a theory. To capture the effect of polarization of peptide linkages on conformational and H-bonding propensity of the polypeptide backbone, we introduce a function of shielding tensors of the Cα atoms. Carrying no information about side chain-side chain interactions, this function nonetheless identifies basic features of the secondary and tertiary structure, establishes sequence correlates of the metamorphic and pH-driven equilibria, relates binding affinities and folding rate constants to secondary structure preferences, and manifests common patterns of backbone density distribution in amyloidogenic regions of Alzheimer’s amyloid β and tau, Parkinson’s α-synuclein and prions. Based on those findings, a split-intein like mechanism of molecular recognition is proposed to underlie dimerization of Aβ, tau, αS and PrPC, and divergent pathways for subsequent association of dimers are outlined; a related mechanism is proposed to underlie formation of PrPSc fibrils. The model does account for: (i) structural features of paranuclei, off-pathway oligomers, non-fibrillar aggregates and fibrils; (ii) effects of incubation conditions, point mutations, isoform lengths, small-molecule assembly modulators and chirality of solid-liquid interface on the rate and morphology of aggregation; (iii) fibril-surface catalysis of secondary nucleation; and (iv) self-propagation of infectious strains of mammalian prions.

The BioFragment Database (BFDb): An open-data platform for computational chemistry analysis of noncovalent interactions.

Accurate potential energy models are necessary for reliable atomistic simulations of chemical phenomena. In the realm of biomolecular modeling, large systems like proteins comprise very many noncovalent interactions (NCIs) that can contribute to the protein's stability and structure. This work presents two high-quality chemical databases of common fragment interactions in biomolecular systems as extracted from high-resolution Protein DataBank crystal structures: 3380 sidechain-sidechain interactions and 100 backbone-backbone interactions that inaugurate the BioFragment Database (BFDb). Absolute interaction energies are generated with a computationally tractable explicitly correlated coupled cluster with perturbative triples [CCSD(T)-F12] "silver standard" (0.05 kcal/mol average error) for NCI that demands only a fraction of the cost of the conventional "gold standard," CCSD(T) at the complete basis set limit. By sampling extensively from biological environments, BFDb spans the natural diversity of protein NCI motifs and orientations. In addition to supplying a thorough assessment for lower scaling force-field (2), semi-empirical (3), density functional (244), and wavefunction (45) methods (comprising >1M interaction energies), BFDb provides interactive tools for running and manipulating the resulting large datasets and offers a valuable resource for potential energy model development and validation.

Self-assembling Morphologies Obtained from Helical Polycarbodiimide Copolymers and Their Triazole Derivatives.

A facile method for the preparation of polycarbodiimide-based secondary structures (e.g., nano-rings, "craters," fibers, looped fibers, fibrous networks, ribbons, worm-like aggregates, toroidal structures, and spherical particles) is described. These aggregates are morphologically influenced by extensive hydrophobic side chain-side chain interactions of the singular polycarbodiimide strands, as inferred by atomic force microscopy (AFM) and scanning electron microscopy (SEM) techniques. Polycarbodiimide-g-polystyrene copolymers (PS-PCDs) were prepared by a combination of synthetic methods, including coordination-insertion polymerization, copper(I)-catalyzed azide alkyne cycloaddition (CuAAC) "click" chemistry, and atom transfer radical polymerization (ATRP). PS-PCDs were found to form specific toroidal architectures at low concentrations in CHCl3. To determine the influence of a more polar solvent medium (i.e., THF and THF/EtOH) on polymer aggregation behavior, a number of representative PS-PCD composites have been tested to show discrete concentration-dependent spherical particles. These fundamental studies are of practical interest to the development of experimental procedures for desirable architectures by directed self-assembly in thin film. These architectures may be exploited as drug carriers, whereas other morphological findings represent certain interest in the area of novel functional materials.

Inherent Conformational Preferences of Ac-Gln-Gln-NHBn: Sidechain Hydrogen Bonding Supports a β-Turn in the Gas Phase.

Gas-phase single-conformation spectroscopy is used to study Ac-Gln-Gln-NHBn in order to probe the interplay between sidechain hydrogen bonding and backbone conformational preferences. This small, amide-rich peptide offers many possibilities for backbone-backbone, sidechain-backbone, and sidechain-sidechain interactions. The major conformer observed experimentally features a type-I β-turn with a canonical 10-membered ring C=O-H-N hydrogen bond between backbone amide groups. In addition, the C=O group of each Gln sidechain participates in a seven-membered ring hydrogen bond with the backbone NH of the same residue. Thus, sidechain hydrogen-bonding potential is satisfied in a manner that is consistent with and stabilizes the β-turn secondary structure. This turn-forming propensity may be relevant to pathogenic amyloid formation by polyglutamine segments in human proteins.

β-Hairpin Crowding Agents Affect α-Helix Stability in Crowded Environments.

The dense, heterogeneous cellular environment is known to affect protein stability. It is now recognized that attractive "quinary" interactions with other biomacromolecules in the cell, referred to as the crowding agents, play a significant role in determining the stability of the protein of interest or test protein. These attractive interactions can reduce or overcome the stabilizing effect of the excluded volume of the crowding agents. However, the roles of specific interactions, such as hydrogen bonding and side chain-side chain hydrophobic interactions, are still unclear. Here, we use molecular simulation to investigate the roles played by hydrophobic interactions and hydrogen bonding between a small helical test protein and equally sized crowding agent proteins in a fixed β-hairpin configuration. The test protein and crowding agents are represented by a coarse-grained protein model, and we use multicanonical molecular dynamics to study the folding thermodynamics of the test protein. Our results confirm that the stability of the test protein depends on the hydrophobicity of the crowding agents and that the stability of the test protein is reduced through favorable side chain-side chain interactions that preferentially stabilize the unfolded states. In addition, we show that when the intermolecular hydrophobic interactions are more favorable than the intramolecular hydrophobic interactions, the β-rich crowding agents can completely destabilize the test protein, causing it to adopt configurations with increased β-content and preventing it from forming its native helical state. Similarities between our results and those seen in the formation of amyloid fibrils are also discussed.

Theoretical Studies of Interactions between O-Phosphorylated and Standard Amino-Acid Side-Chain Models in Water.

Phosphorylation is a common post-translational modification of the amino-acid side chains (serine, tyrosine, and threonine) that contain hydroxyl groups. The transfer of the negatively charged phosphate group from an ATP molecule to such amino-acid side chains leads to changes in the local conformations of proteins and the pattern of interactions with other amino-acid side-chains. A convenient characteristic of the side chain-side chain interactions in the context of an aqueous environment is the potential of mean force (PMF) in water. A series of umbrella-sampling molecular dynamic (MD) simulations with the AMBER force field were carried out for pairs of O-phosphorylated serine (pSer), threonine (pThr), and tyrosine, (pTyr) with natural amino acids in a TIP3P water model as a solvent at 298 K. The weighted-histogram analysis method was used to calculate the four-dimensional potentials of mean force. The results demonstrate that the positions and depths of the contact minima and the positions and heights of the desolvation maxima, including their dependence on the relative orientation depend on the character of the interacting pairs. More distinct minima are observed for oppositely charged pairs such as, e.g., O-phosphorylated side-chains and positively charged ones, such as the side-chains of lysine and arginine.

Investigation of the β-sheet interactions between dHP1 chromodomain and histone 3.

Methylated lysine 9 on the histone 3 (H3) tail recruits heterochromatin protein 1 from Drosophila (dHP1) via its chromodomain and results in gene silencing. The dHP1 chromodomain binds H3 K9Me3 with an aromatic cage surrounding the trimethyllysine. The sequence selectivity of binding comes from insertion of the histone tail between two β-strands of the chromodomain to form a three-stranded β-sheet. Herein, we investigated the sequence selectivity provided by the β-sheet interactions and how those interactions compare to other model systems. Residue Thr6 of the histone tail forms cross-strand interactions with Ala25 and Asp62 of the chromodomain. Each of these three residues was substituted for amino acids known to have high β-sheet propensities and/or to form favorable side chain-side chain (SC-SC) interactions in β-sheets, including hydrophobic, H-bonding, and aromatic interactions. We found that about 50% of the chromodomain mutants resulted in equal or tighter binding to the histone tail and about 25% of the histone tail mutants provided tighter binding compared to that of the native histone tail sequence. These studies provide novel insights into the sequence selectivity of the dHP1 chromodomain for the histone tail and relates the information gleaned from model systems and statistical studies to β-sheet-mediated protein-protein interactions. Moreover, this work suggests that the development of designer histone-chromodomain pairs for chemical biology applications is feasible.

Local and macroscopic electrostatic interactions in single α-helices.

The noncovalent forces that stabilize protein structures are not fully understood. One way to address this is to study equilibria between unfolded states and α-helices in peptides. Electrostatic forces-which include interactions between side chains, the backbone and side chains, and side chains and the helix macrodipole-are believed to contribute to these equilibria. Here we probe these interactions experimentally using designed peptides. We find that both terminal backbone-side chain and certain side chain-side chain interactions (which include both local effects between proximal charges and interatomic contacts) contribute much more to helix stability than side chain-helix macrodipole electrostatics, which are believed to operate at larger distances. This has implications for current descriptions of helix stability, the understanding of protein folding and the refinement of force fields for biomolecular modeling and simulations. In addition, this study sheds light on the stability of rod-like structures formed by single α-helices, which are common in natural proteins such as non-muscle myosins.

Protein-protein interactions affect alpha helix stability in crowded environments.

The dense, heterogeneous cellular environment is known to affect protein stability through interactions with other biomacromolecules. The effect of excluded volume due to these biomolecules, also known as crowding agents, on a protein of interest, or test protein, has long been known to increase the stability of a test protein. Recently, it has been recognized that attractive protein-crowder interactions play an important role. These interactions affect protein stability and can destabilize the test protein. However, most computational work investigating the role of attractive interactions has used spherical crowding agents and has neglected the specific roles of crowding agent hydrophobicity and hydrogen bonding. Here we use multicanonical molecular dynamics and a coarse-grained protein model to study the folding thermodynamics of a small helical test protein in the presence of crowding agents that are themselves proteins. Our results show that the stability of the test protein depends on the hydrophobicity of the crowding agents. For low values of crowding agent hydrophobicity, the excluded volume effect is dominant, and the test protein is stabilized relative to the dilute solution. For intermediate values of the crowding agent hydrophobicity, the test protein is destabilized by favorable side chain-side chain interactions stabilizing the unfolded states. For high values of the crowding agent hydrophobicity, the native state is stabilized by the strong intermolecular attractions, causing the formation of a packed structure that increases the stability of the test protein through favorable side chain-side chain interactions. In addition, increasing crowding agent hydrophobicity increases the "foldability" of the test protein and alters the potential energy landscape by simultaneously deepening the basins corresponding to the folded and unfolded states and increasing the energy barrier between them.

Protein-Protein Interactions Affect Native State Stability in Crowded Environments

The dense, heterogeneous cellular environment is known to affect protein stability through interactions with other biomacromolecules. The effect of excluded volume due to these biomolecules, also known as crowding agents, on a protein of interest, or test protein, has long been known to increase the stability of a test protein. Recently, it has been recognized that attractive protein-crowder interactions play an important role. These interactions affect protein stability and can destabilize the test protein. However, most computational work investigating the role of attractive interactions has used spherical crowding agents and has neglected the specific roles of crowding agent hydrophobicity and hydrogen bonding. Here, we use multicanonical molecular dynamics and a coarse-grained protein model to study the folding thermodynamics of a small helical test protein in the presence of crowding agents that are themselves proteins. Our results show that the stability of the test protein depends on the hydrophobicity of the crowding agents. For low values of crowding agent hydrophobicity, the excluded volume effect is dominant and the test protein is stabilized relative to the dilute solution. For intermediate values of the crowding agent hydrophobicity, the test protein is destabilized by favorable side chain-side chain interactions stabilizing the unfolded states. For high values of the crowding agent hydrophobicity, the native state is stabilized by the strong intermolecular attractions causing the formation of a packed structure that increases the stability of the test protein through favorable side chain-side chain interactions. In addition, increasing crowding agent hydrophobicity increases the “foldability” of the test protein and alters the potential energy landscape by simultaneously deepening the basins corresponding to the folded and unfolded states and increasing the energy barrier between them.

Altered Backbone and Side-Chain Interactions Result in Route Heterogeneity during the Folding of Interleukin-1β (IL-1β)

Deletion of the β-bulge trigger-loop results in both a switch in the preferred folding route, from the functional loop packing folding route to barrel closure, as well as conversion of the agonist activity of IL-1β into antagonist activity. Conversely, circular permutations of IL-1β conserve the functional folding route as well as the agonist activity. These two extremes in the folding-functional interplay beg the question of whether mutations in IL-1β would result in changes in the populations of heterogeneous folding routes and the signaling activity. A series of topologically equivalent water-mediated β-strand bridging interactions within the pseudosymmetric β-trefoil fold of IL-1β highlight the backbone water interactions that stabilize the secondary and tertiary structure of the protein. Additionally, conserved aromatic residues lining the central cavity appear to be essential for both stability and folding. Here, we probe these protein backbone-water molecule and side chain-side chain interactions and the role they play in the folding mechanism of this geometrically stressed molecule. We used folding simulations with structure-based models, as well as a series of folding kinetic experiments to examine the effects of the F42W core mutation on the folding landscape of IL-1β. This mutation alters water-mediated backbone interactions essential for maintaining the trefoil fold. Our results clearly indicate that this perturbation in the primary structure alters a structural water interaction and consequently modulates the population of folding routes accessed during folding and signaling activity.

Gas-phase salt bridge interactions between glutamic acid and arginine

The gas-phase side chain-side chain (SC-SC) interaction and possible proton transfer between glutamic acid (Glu) and arginine (Arg) residues are studied under low-temperature conditions in an overall neutral peptide. Conformation-specific IR spectra, obtained with the free electron laser FELIX, in combination with density functional theory (DFT) calculations, provide insight into the occurrence of intramolecular proton transfer and detailed information on the conformational preferences of the peptides Z-Glu-Alan-Arg-NHMe (n = 0,1,3). Low-energy structures are obtained using molecular dynamics simulations via the simulated annealing approach, resulting in three types of SC-SC interactions, in particular two types of pair-wise interactions and one bifurcated interaction. These low-energy structures are optimized and frequency calculations are performed using the B3LYP functional, for structural analysis, and the M05-2x functional, for relative energies, employing the 6-311+G(d,p) basis set. Comparison of experimental and computed spectra suggests that only a single conformation was present for each of the three peptides. Despite the increasing spacing between the Glu and Arg residues, the peptides have several types of interactions in common, in particular specific SC-SC and dispersion interactions between the Arg side chain and the phenyl ring of the Z-cap. Comparison with previous experiments on Ac-Glu-Ala-Phe-Ala-Arg-NHMe as well as molecular dynamics simulations further suggest that the pairwise interaction observed here is indeed energetically most favorable for short peptide sequences.

Protein secondary structure mimetics: crystal conformations of α/γ4-hybrid peptide12-helices with proteinogenic side chains and their analogy with α- and β-peptide helices

Numerous strategies have been developed to mimic the α-helical secondary structure using hybrid peptides containing non-natural amino acids. In contrast to the β- and α/β-hybrid peptides, very little is known about the folding patterns of hybrid peptides containing γ(4)-amino acids. Here we report the solid phase synthesis and crystallographic insight into the secondary structures formed by 1 : 1 alternating α/γ(4)-hybrid peptides. The crystal conformations suggest that heptapeptides P1, P2 and P3 adopted the 12-helix conformation with backward consecutive 1←4 H-bonds [C=O(i)···H-N (i + 3)]. In comparison with α-, β- and γ-peptides, the distinct projection of side-chains was observed along the helical cylinder. In contrast to the peptide containing stereochemically constrained α-amino acid Aib (P1), the peptide with complete proteinogenic side-chains (P3) displayed organized side chain-side chain interactions between the antiparallel helices in crystal packing. The analogy of the α/γ(4)-hybrid peptides with 3(10)-helix, α-helix and β-peptide 12-helix suggests that the internal H-bonding pattern and macrodipole were analogous to the α- and β-peptide helices. In addition, helical parameters were found to be very similar to that of β-peptide 12-helices.