key: cord-0268691-8a8otjsz
authors: Sikdar, Samapan; Banerjee, Manidipa; Vemparala, Satyavani
title: Role of Disulfide Bonds in Membrane Partitioning of a Viral Peptide
date: 2021-09-21
journal: bioRxiv
DOI: 10.1101/2021.09.21.461184
sha: bd2ca9388f0d0c43dc8cc10824642aab94c106f4
doc_id: 268691
cord_uid: 8a8otjsz

The importance of disulfide bond in mediating viral peptide entry into host cells is well known. In the present work, we elucidate the role of disulfide (SS) bond in partitioning mechanism of membrane active Hepatitis A Virus-2B (HAV-2B) peptide, which harbours three cysteine residues promoting formation of multiple SS-bonded states. The inclusion of SS-bond not only results in a compact conformation but also induces distorted α-helical hairpin geometry in comparison to SS-free state, resulting in reduced hydrophobic exposure. Owing to this, the partitioning of HAV-2B peptide is completely or partly abolished. In a way, the disulfide bond regulates the partitioning of HAV-2B peptide, such that the membrane remodelling effects of this viral peptide are significantly reduced. The current findings may have potential implications in drug designing, targeting the HAV-2B protein by promoting disulfide bond formation within its membrane active region.

Disulfide (SS) bond formation involves oxidation of thiol (SH) groups of two spatially proximal cysteine residues leading to a covalent linkage between their side-chains. The thioldisulfide exchange reaction, regulated by oxidoreductases, like thioredoxin and protein disulfide isomerise (PDI), [1] predominantly occurs in endoplasmic reticulum and occasionally at other cellular sites. [2] The presence of disulfide bonds contribute to both protein structure and function by inducing conformational stability, facilitating protein folding and assembly, sensing changes in redox environment to modulate protein activity and localization. [1, 2] This plethora of functions illustrates the importance of disulfide bonds in both secretory and membrane proteins, like, Prion [3, 4] , Src family kinases [5] , Voltage-Dependent Anion Channel [6] , GPCRs [7] to name a few.

Membrane active peptides often harbour multiple cysteine residues, which may remain in reduced thiol state or in oxidized disulfide linked state. [8] Several studies have highlighted the role of redox status of cysteine residues in modulating permeability of these membrane active peptides. [1, 9] For instance, antimicrobial peptides belonging to defensin family, characterized by presence of three intra-molecular SS-bridges, have been vastly studied in context of host defence mechanism against virulent microbes, by varying the number of disulfide bond and their native connectivity. [10] [11] [12] [13] [14] Experiments reveal enhanced antimicrobial activity upon reduction of SS-bonds of Human   defensin 1 (hBD-1) [10] and hBD-4 [11] . Further, molecular dynamics (MD) simulation studies of hBD-3 analogs lacking SS-linkages induce significant disruption of negatively charged lipid bilayers, compared to their native counter-part. [13] Similarly, the antimicrobial activity of other disulfide rich peptides has been known to be regulated by presence / absence of SS-bonds. [15] [16] [17] [18] 4 Environment dependent thiol-disulfide switching plays important role in mediating virus entry into cells. [9] In this regard, it is required for Human immunodeficiency virus-1 (HIV-1) envelope protein dissociate into two subunits namely, gp120 and gp41, upon interaction with host cell receptors followed by reduction of redox active SS-bonds to allosterically unmask membrane active fusion peptide initiating membrane insertion. [9, [19] [20] [21] [22] Such thiol-disulfide exchange mediated exposure and subsequent insertion of fusion peptide has been reported for other viruses as well. [23] [24] [25] [26] [27] [28] [29] On other hand, the presence of disulfide bonds within the membrane active region of reovirus p10 fusion-associated small transmembrane (FAST) proteins [30, 31] and of Ebola virus delta-peptide [32, 33] are quintessential for membrane permeation as demonstrated in recent studies.

Motivated by these studies, we investigate the role of disulfide bond in regulating membrane partitioning of Hepatitis A virus (HAV) 2B protein. [34] Compared to 2B proteins of other picornaviruses, the HAV-2B is unusually longer and shares limited (< 20 %) sequence similarity with them. [35, 36] It plays a vital role in membrane remodelling [37] and viral replication [38] , but does not participate in calcium homeostasis or host membrane trafficking [36] . The HAV-2B protein is mainly localized in endoplasmic reticulum membrane and partly in mitochondrial, golgi bodies and plasma membrane. [39] The membrane active part, 60 amino acids long, located at C-terminal region of HAV-2B protein [39] , is characterized by presence of multiple cysteine residues. Experimental demonstrations based on biophysical techniques and biochemical assays in membrane mimicking conditions indicated an   helical conformation exhibiting lipid type and composition dependent membrane permeabilizing property. [39] In our previous study [40] based on extensive all-atom MD simulations, we provided insight into HAV-2B peptide induced membrane response as a function of lipid type and composition. 

The HAV-2B membrane active viral peptide is 60 amino acids long and harbours three cysteine (C11, C47 and C52) residues (Fig 1) . These cysteine residues may remain in reduced thiol state or in oxidized state, where two such residues are bonded through a disulfide linkage, resulting in three possible SS-bonded states of HAV-2B peptide denoted as SS11-47, SS11-52

and SS47-52. Owing to unavailability of experimentally determined structure, the membrane active region of HAV-2B peptide has been modelled in a recent study [39] and further refined through extensive molecular dynamics (MD) simulations in water, details of which are provided in our earlier study [40] . We consider representative MD snapshots of SS-free state of HAV-2B

peptide in water to model the SS-bonded states. The snapshots are so chosen such that a pair of cysteine residues in close proximity (~ 5 Å) can form SS-bond between them. The modelled disulfide bonded peptides are further energy minimized over 5000 steps using the conjugate gradient algorithm in NAMD2.10 [42] . We place these energy minimized SS-bonded peptides MD simulations for each of these systems (see SI Table S1 ) are performed in NAMD2.10 [42] using modified TIP3P [43] water model, CHARMM36m [44] and CHARMM36 [45] force field parameters for the peptide and the lipid molecules, respectively. All systems are energy Dynamics (VMD) [46] , MEMBPLUGIN [47] , Packmem [48] and in-house Fortran codes.

The MD simulation of disulfide free HAV-2B peptide in water from our previous study [40] , indicate close spatial proximity of cysteine residues, namely C11, C47 and C52, 

The molecular dimension of HAV-2B peptide is characterized by probability distribution of radius of gyration,   Fig 1D) and SS11-52 ( Fig 1E) peptides, while, the linkage is confined within the C-terminal tail of SS47-52 peptide. Despite the differences in location and connectivity, these disulfide bonds act as a constraint reducing the overall conformational fluctuations of the peptide.

We also characterize the conformational preference in terms of the helical arrangement of the hairpin structure through inter-helical angle,  . The vector between C-α atoms of L18 and I22 represents the first helical axis, while that of L36 and M40 represents the second,  being the angle between them (see Fig 1D) . The equilibrium distributions,   overlapping with  lying between 140° -150°, resembling a "boomerang" conformation. In contrast, the distribution of inter-helical angle of SS47-52 peptide about  ~ 160° is quite similar to that of SS-free state (  ~ 170°) resembling a near anti-parallel helical conformation characteristic of a hairpin structure. The SS-linkage between the two terminals thus controls the inter-helical angle in a way so as to distort the hairpin geometry of both SS11-47 and SS47-52 states; whereas the geometry is almost preserved when the linkage is confined within the Cterminal tail of SS47-52 peptide.

The secondary structure of disulfide bonded HAV-2B peptides are calculated using the STRIDE [49] algorithm implemented in VMD [46] . The residue-wise secondary structure percentage (see SI, Fig S2) represents the population of different structural elements explored by each residue during the course of simulation. The residues I17 to L25 and H30 to Y42 form the two  -helices of the hairpin motif of the SS-bonded states. The overall secondary structure percentage remains qualitatively similar across different SS-bonded states. The N-and Cterminal tail residues are predominantly characterized by "turn" or random "coil"

conformations, with few residues showing minor populations of  -helix,  -sheets, and strands.

We also compare the changes in secondary structure population of the cysteine residues in different SS-bonded states (Fig 2A-C) with that of SS-free state. C11 (Fig 2A) predominantly exhibits random "coil" conformation in SS-free as well as in SS47-52 states. But whenever, C11 is involved in SS-bond formation as in SS11-47 and SS11-52 states, the propensity to adopt random "coil" conformation decreases with an increase in "turn" like secondary structural element. Similarly, random "coil" conformation of C47 (Fig 2B) is prevalent in SS-free and SS11-52 states, but enhanced population of "turn" is observed in SS11-47 and SS47-52 states.

Our observations indicate that the cysteine residues upon being involved in SS-bonding generally show a shift in conformational equilibrium towards "turn" like secondary structure component from random "coil" conformation, the only exception being increased "coil" propensity for C52 ( Fig 2C) in SS11-52 state. The presence of disulfide bond significantly alters the secondary structure propensity of a triad of residues, namely, H30-S31-H32 (see Fig 2D-F) , the location of this triad is indicated in Fig 1D-F . The residue triad forms part of the inter-helical flexible linker in SS-free state and shows transition between "turn" and 10 3 -helices. In contrast, these residues adopt an  -helical conformation all throughout the SS-bonded states (Fig 2D-F) . The change in conformational equilibrium of H30-S31-H32 from flexible "turn" / 10 3 -helical to more rigid helical conformation possibly accounts for the observed deviation in inter-helical angles (Fig 1C) of SS-bonded states from that of SS-free state. 

We observe significant differences in mode of peptide binding to POPC bilayer depending on disulfide connectivity (Fig 3) . The SS11-47 peptide interacts with POPC membrane (Fig 3A) through its C-terminal region. The α-helical hairpin motif orients itself almost parallel to membrane normal (z-direction) and remains solvent exposed including the N- peptide hovers close to membrane surface but fails to form any stable contacts with POPC membrane (Fig 3B) within our simulation time-scale of 500 ns. As a consequence, the peptide residues remain far (~ 40 Å) from bilayer centre (Fig 1E) . The binding mode of SS47-52 peptide with POPC membrane is shown in Fig 3C. Unlike SS11-47 peptide, the α-helical hairpin motif orients itself parallel to bilayer resulting in enhanced contact surface area. The SS47-52 peptide interacts with the membrane by complete insertion of N-terminal helix (I17 -L25) and the preceding tail, the average insertion depth being ~ 10 -15 Å (Fig 1F) . The C-terminal helix (H30 -Y42) of the hairpin motif and the succeeding tail region, although solvent exposed, are located close to the POPC headgroups.

13 In this regard, it is also interesting to study the partitioning of cysteine residues. The density peaks of disulfide bonded cysteine pairs in SS11-47 ( Fig 3D) and SS47-52 ( Fig 3F) states are located at the solvent proximal interface very close to the lipid headgroups. While the other cysteine in reduced thiol state: C52 of SS11-47 ( Fig 3A) and C11 of SS47-52 ( Fig 3C) peptides remain embedded in the hydrophobic membrane core. This is in agreement to a recent study, which concluded that cysteine residues in reduced thiol state favourably partitions into the hydrophobic membrane milieu rather than at the polar lipid-water interface. [50] 

We and bilayer thickness (~ 35.6 Å) is also observed to be intermediate between that of SS-free peptide and control POPC bilayers. [40] We illustrate the 2d-thickness profiles (Fig 4C-D) along the membrane xy-plane corresponding to final snapshots (Fig 4E-F) Owing to the reduced partitioning of HAV-2B peptide in presence of SS-bond, the membrane perturbation effects are also significantly reduced. The membrane thinning effect is localized around the insertion site of SS47-52 peptide, while more pronounced uniform global thinning effect is observed upon SS-free HAV-2B peptide partitioning.

The membrane response is not only restricted to lipid acyl tails, but also extend to the bilayer-water interface in the form of lipid headgroups packing. This interfacial region is characterized by transient exposure of membrane hydrophobic core to hydration layer, leading to lipid packing defects which act as binding hotspots for peptides. [51] [52] [53] [54] [55] [56] [57] [58] [59] [60] These lipid packing defects are qualitatively characterized into "Deep" or "Shallow" depending on the relative depth of the defect site with respect to the nearest glycerol backbone and further quantified by area ( A ) of the defect site, following the standard protocol using Packmem [48] . The distribution of defect sites based on their size exhibit single exponential decay,    

The decay constant,  , characteristically describes the membrane topology in terms of interfacial defects:

The higher the value of  , the more abundant are large defect sites.

The size distribution of "Deep" defect sites is shown in SI, Fig S4A, Table S2 , indicate similar values varying between 10 -12 Å 2 . The size distributions of "Shallow" defects, shown in SI, Fig S4B, are also similar for all SS-bonded peptides with Shallow  varying between 15 -17 Å 2 (see Table S2 ). Upon comparing the size distributions,   A P of both "Deep" and "Shallow" defects, we observe that the number of defect 18 sites as well as the occurrence of larger defect sites increase in presence of SS-bonded peptides with respect to control POPC bilayer. However, this abundance of defect sites is much more pronounced under the influence of SS-free HAV-2B peptide, as also evident from higher defect area constants listed in Table S2 . While "Deep" defects are affected by partitioning of bulky hydrophobic residues, "Shallow"

defects are known to be influenced by presence of short chain hydrophobic amino acids, as reported for   Synuclein. [54, 56] The N-terminal helix of hairpin motif and the preceding tail 20 harbours few such small hydrophobic residues, while the majority of them reside at the Cterminal helix and the succeeding tail. Owing to this, the partitioning of N-terminal helix of SS47-52 does not affect the "Shallow" defects. On contrary, both the helices and the C-terminal tail of SS-free peptide being involved in membrane partitioning, enhances the "Shallow" defects.

Our previous study indicated that the SS-free HAV-2B peptide senses membrane topography in the form of lipid packing defects, inserts into such defects and subsequently partitions into POPC bilayer. [40] In this section, we elucidate the mechanism of partitioning of SS47-52 state of the viral peptide. We consider a representative set of residues, C11 (red), L18

(cyan) and L25 (green) of SS47-52 peptide (Fig 5C) , which undergo deep insertion into POPC membrane. The insertion dynamics of these residues are monitored from the individual distance (z-distance) of residue centre of mass from the average level of C2 atoms of glycerol moieties in POPC molecule, along the z-direction. A negative value of z-distance implies insertion below the average C2 level. Simultaneously, we track the appearance of any underlying "Deep" lipid packing defect that is co-localized with these residues. In the process, we identify a single large co-localized "Deep" defect in vicinity of these residues. The defect area fluctuating around 250 Å 2 drives the residue insertions at around 350 ns, following which the co-localized "Deep" defect area momentarily increases to 400 Å 2 to accommodate the bulky hydrophobic side-chains.

The insertion of SS47-52 peptide into the co-localized "Deep" defect is illustrated through a representative snapshot in Fig 5D. 

The present study provides insight into the effect of disulfide bond on HAV-2B peptide structure and partitioning into membrane. The inclusion of SS-bond not only results in a compact conformation but also changes the inter-helical angle,  , resulting in deviation from hairpin conformation in comparison to SS-free state. The anti-parallel hairpin arrangement of α-helices is known to be essential for membrane partitioning of viral peptide as reported for Influenza virus hemagglutinin [61] and Ebola virus delta peptide [33] . The change in inter-helical angle, which in turn modulates helix packing interactions along with the compact conformation of SSbonded states control the accessible surface area (ASA) of the peptide (Fig 6A) We illustrate the hydrophobic (green) and hydrophilic (magenta) ASA of HAV-2B peptide in SS-free ( Fig 6B) and bound states (Fig 6C-E) . In SS-free state, the peptide presents an exposed hydrophobic dominated face and a hydrophilic dominated opposite surface (Fig 6B) .

The conformation of SS-free HAV-2B peptide is such that it acquires a strong facially 23 amphipihilic character upon segregation of hydrophobic and hydrophilic residues. Different membrane active agents including antimicrobial peptides [55, 62, 63] , polymers [58, [64] [65] [66] [67] [68] [69] and other membrane active molecules [70] [71] [72] are known to acquire such amphipihilic conformations upon partitioning into cellular membranes. However, in SS11-47 ( Fig 6C) and SS11-52 (Fig 6D) states, the hydrophobic accessible surface area is limited resulting in mitigation of peptide partitioning. On other hand, the segregation of hydrophobic and hydrophilic surfaces is not as discrete as that in SS-free state, leading to partial partitioning of SS47-52 peptide (Fig 6E) . The disulfide bond induced conformational changes thus control the exposure of hydrophobic residues, which in turn regulates HAV-2B peptide partitioning. As a consequence the SS-bonded peptide induced membrane responses, in terms of lipid tail disordering, membrane thinning and abundance of interfacial packing defects, are mild compared to the SS-free state. In a way, the disulfide bond regulates the membrane active property of HAV-2B peptide, such that the membrane destabilizing effects of this viral peptide are significantly reduced.

Evidence of thiol-disulfide redox status dependent exposure of hydrophobic patches facilitating peptide partitioning is well documented through experimental investigations on different membrane active agents like antimicrobial peptides [10, 11, 13, 17] and viral fusion peptides [21, [23] [24] [25] [26] [27] [28] [29] 31] . This importance of disulfide bond in mediating viral peptide partitioning and subsequent entry into host cells is currently being explored to design antiviral agents. For instance, reduction of disulfide bond by PDI being pre-requisite for HIV entry, designing inhibitors targeting this process interferes with the virus / cell fusion mechanism. [9, [19] [20] [21] Similar efforts are in progress to develop therapeutics against coronavirus infection. [41] The present findings indicate that promoting disulfide bond formation within the membrane active 24 HAV-2B peptide may have potential implications in designing antiviral agents to combat HAV infection.

The presence of multiple cysteine residues in the membrane active region of HAV-2B peptide indicates the possibility of three SS-bonded states of the peptide. In the present work, we elucidate the role of disulfide bond in HAV-2B peptide partitioning. The SS-linkage induces shrinking of peptide conformation as well as distortion of its α-helical hairpin geometry, resulting in reduced hydrophobic exposure. Depending on disulfide connectivity, the partitioning of HAV-2B peptide is completely or partly abolished and subsequently reduced membrane remodelling effects are observed in comparison to SS-free state. The disulfide bond thus regulates the membrane active property of the viral peptide. These results may find potential applications in drug designing approaches against HAV infection.

SS, MB and SV designed the project. SS performed the simulations and carried out the analysis.

All authors contributed to writing and reviewing the manuscript.

From structure to redox: The diverse functional roles of disulfides and implications in disease

Cysteines and Disulfide Bonds as Structure-Forming Units: Insights From Different Domains of Life and the Potential for Characterization by NMR

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Disulfide Bond as a Structural Determinant of Prion Protein Membrane Insertion

Structural insights into redox-active cysteine residues of the Src family kinases

A computational study of ion current modulation in hVDAC3 induced by disulfide bonds

Lifting the lid on GPCRs: the role of extracellular loops

Cell-Penetrating Peptides: Design Strategies beyond Primary Structure and Amphipathicity

Cell Entry by Enveloped Viruses: Redox Considerations for HIV and SARS-Coronavirus

Reduction of disulphide bonds unmasks potent antimicrobial activity of human β-defensin 1

Human β-Defensin 4 with Non-Native Disulfide Bridges Exhibit Antimicrobial Activity

Integrated solid-state NMR and molecular dynamics modeling determines membrane insertion of human β-defensin analog

Disulfide Bonds Affect the Binding Sites of Human β Defensin Type 3 on Negatively Charged Lipid Membranes

Molecular Dynamics Simulations of Human Beta-Defensin Type 3 Crossing Different Lipid Bilayers

Peptide-lipid interactions of the β-hairpin antimicrobial peptide tachyplesin and its linear derivatives from solid-state NMR

Implicit Membrane Investigation of the Stability of Antimicrobial Peptide β-Barrels and Arcs

Influences of disulfide connectivity on structure and antimicrobial activity of tachyplesin I

Experimental and Computational Characterization of Oxidized and Reduced Protegrin Pores in Lipid Bilayers

Inhibitors of Protein-Disulfide Isomerase Prevent Cleavage of Disulfide Bonds in Receptor-bound Glycoprotein 120 and Prevent HIV-1 Entry *

Protein-disulfide Isomerase-mediated Reduction of Two Disulfide Bonds of HIV Envelope Glycoprotein 120 Occurs Post-CXCR4 Binding and Is Required for Fusion *

Redox-Triggered Infection by Disulfide-Shackled Human Immunodeficiency Virus Type 1 Pseudovirions

Viral envelope protein folding and membrane hemifusion are enhanced by the conserved loop region of HIV-1 gp41

Sindbis virus membrane fusion is mediated by reduction of glycoprotein disulfide bridges at the cell surface

Murine coronavirus membrane fusion is blocked by modification of thiols buried within the spike protein

An unconventional role for cytoplasmic disulfide bonds in vaccinia virus proteins

Isomerization of the intersubunit disulphide-bond in Env controls retrovirus fusion

Thiol/disulfide exchange is required for membrane fusion directed by the Newcastle disease virus fusion protein

Disulfide-bond formation by a single cysteine mutation in adenovirus protein VI impairs capsid release and membrane lysis

Reversible Inhibition of Fusion Activity of a Paramyxovirus Fusion Protein by an Engineered Disulfide Bond in the Membrane-Proximal External Region

Features of a Spatially Constrained Cystine Loop in the p10 FAST Protein Ectodomain Define a New Class of Viral Fusion Peptides*

The p10 FAST protein fusion peptide functions as a cystine noose to induce cholesterol-dependent liposome fusion without liposome tubulation

Ebola Virus Delta Peptide Is a Viroporin

Membrane pore formation and ion selectivity of the Ebola virus delta peptide

Structural basis for host membrane remodeling induced by protein 2B of hepatitis A virus

Mechanisms of membrane permeabilization by picornavirus 2B viroporin

Functional analysis of picornavirus 2B proteins: effects on calcium homeostasis and intracellular protein trafficking

Membrane permeability induced by hepatitis A virus proteins 2B and 2BC and proteolytic processing of HAV 2BC

Importance of amino acid 216 in nonstructural protein 2B for replication of hepatitis A virus in cell culture and in vivo

The C-terminal region of the non-structural protein 2B from Hepatitis A Virus demonstrates lipid-specific viroporin-like activity

Effect of cholesterol on the membrane partitioning dynamics of hepatitis A virus-2B peptide

Role of Oxidative Stress on SARS-CoV (SARS) and SARS-CoV-2 (COVID-19) Infection: A Review

Scalable molecular dynamics with NAMD

Comparison of simple potential functions for simulating liquid water

CHARMM36m: an improved force field for folded and intrinsically disordered proteins

Update of the CHARMM All-Atom Additive Force Field for Lipids: Validation on Six Lipid Types

VMD: visual molecular dynamics

MEMBPLUGIN: studying membrane complexity in VMD

PackMem: A Versatile Tool to Compute and Visualize Interfacial Packing Defects in Lipid Bilayers

Knowledge-based protein secondary structure assignment

Hydrophobic Characteristic Is Energetically Preferred for Cysteine in a Model Membrane Protein

Mechanism of membrane curvature sensing by amphipathic helix containing proteins

alpha-Synuclein senses lipid packing defects and induces lateral expansion of lipids leading to membrane remodeling

Amphipathic lipid packing sensor motifs: probing bilayer defects with hydrophobic residues

Lipid cell biology. Polyunsaturated phospholipids facilitate membrane deformation and fission by endocytic proteins

A sub-nanometre view of how membrane curvature and composition modulate lipid packing and protein recruitment

Methylbranched lipids promote the membrane adsorption of alpha-synuclein by enhancing shallow lipidpacking defects

Reovirus FAST Proteins Drive Pore Formation and Syncytiogenesis Using a Novel Helix-Loop-Helix Fusion-Inducing Lipid Packing Sensor

Influence of lipid composition of model membranes on methacrylate antimicrobial polymer-membrane interactions

Structure and Dynamics of the Acyl Chains in the Membrane Trafficking and Enzymatic Processing of Lipids

Effect of Membrane Lipid Packing on Stable Binding of the ALPS Peptide

Charged N-terminus of Influenza Fusion Peptide Facilitates Membrane Fusion

Antimicrobial Peptides in Action

Sequence-Dependent Interaction of β-Peptides with Membranes

Cationic Spacer Arm Design Strategy for Control of Antimicrobial Activity and Conformation of Amphiphilic Methacrylate Random Copolymers

Antimicrobial Polymers: Molecular Design as Synthetic Mimics of Host-Defense Peptides

Interaction of multiple biomimetic antimicrobial polymers with model bacterial membranes

Chapter Four -Membrane-Bound Conformations of Antimicrobial Agents and Their Modes of Action

Macromolecular-clustered facial amphiphilic antimicrobials

Towards designing globular antimicrobial peptide mimics: role of polar functional groups in biomimetic ternary antimicrobial polymers

Partitioning of anesthetics into a lipid bilayer and their interaction with membrane-bound peptide bundles

Partitioning of ethanol in multi-component membranes: effects on membrane structure

Interdigitation of Lipids Induced by Membrane-Active Proteins

All simulations in this work have been carried out on supercomputing facility Nandadevi cluster at The Institute of Mathematical Sciences, Chennai, India.

The authors declare no conflict of interest