Multidimensional free energy surface of unfolding of HP-36: Microscopic origin of ruggedness

The protein folding funnel paradigm suggests that folding and unfolding proceed as directed diffusion in a multidimensional free energy surface where a multitude of pathways can be traversed during the protein's sojourn from initial to final state. However, finding even a single pathway, with the detail chronicling of intermediates, is an arduous task. In this work we explore the free energy surface of unfolding pathway through umbrella sampling, for a small globular a-helical protein chicken-villin headpiece (HP-36) when the melting of secondary structures is induced by adding DMSO in aqueous solution. We find that the unfolding proceeds through the initial separation or melting of aggregated hydrophobic core that comprises of three phenylalanine residues (Phe7, Phe11, and Phe18). This separation is accompanied by simultaneous melting of the second helix. Unfolding is found to be a multistage process involving crossing of three consecutive minima and two barriers at the initial stage. At a molecular level, Phe18 is observed to reorient itself towards other hydrophobic grooves to stabilize the intermediate states. We identify the configuration of the intermediates and correlate the intermediates with those obtained in our previous works. We also give an estimate of the barriers for different transition states and observe the softening of the barriers with increasing DMSO concentration. We show that higher concentration of DMSO tunes the unfolding pathway by destabilizing the third minimum and stabilizing the second one, indicating the development of a solvent modified, less rugged pathway. The prime outcome of this work is the demonstration that mixed solvents can profoundly transform the nature of the energy landscape and induce unfolding via a modified route. A successful application of Kramer's rate equation correlating the free energy simulation results shows faster rate of unfolding with increasing DMSO concentration. This work perhaps presents the first systematic theoretical study of the effect of a chemical denaturant on the microscopic free energy surface and rates of unfolding of HP-36. (C) 2014 AIP Publishing LLC.

Phthalate mediated hydrogelation of a pyrene based system: a novel scaffold for shape-persistent, self-healing luminescent soft material

Two-component super-hydrogelation triggered by the acid-base interaction of a L-histidine appended pyrenyl derivative (PyHis) and phthalic acid (PA) was reported. The use of isomeric isophthalic or terephthalic acid or other comparable acids in place of PA does not lead to salt formation and therefore hydrogelation is not observed. Excimer formation of the pyrenyl unit has not been detected although the PyHis : PA = 1: 1 system undergoes extensive self-assembly in aqueous solution. The synergistic effect of intermolecular H-bonding forces, pi-pi stacking, electrostatic interactions, etc. is found to be responsible for robust hydrogel formation. Development of chiral supramotecular assemblies has been verified through circular dichroism spectroscopy. Morphological investigations involving the PyHis : PA = 1: 1 system show vesicular nano-structures with a definite bilayer width at relatively low concentrations. The latter fuses to construct coiled-coil left-handed helical fibers upon increase in the concentrations of the gelators. The intertwining of the resultant helical fibers eventually results in hydrogel formation. The probable bilayer packing in the self-assembled structures has been probed using X-ray diffraction (XRD) studies and lanthanide sensitization, which suggests that the polar imidazolium hydrogen phthalate unit of the gelator forms the head group and faces the hydrophilic water environment while the hydrophobic pyrenyl units sit inside the hydrophobic core of the bilayer. The hydrogel exhibits multi-stimuli responsiveness including thixotropic behavior. In addition, shape-persistent as well as rapid self-healing behaviour of the hydrogel was established. Furthermore load-bearing characteristics of the hydrogel have also been demonstrated.

Sequence and conformational preferences at termini of alpha-helices in membrane proteins: Role of the helix environment

-helices are amongst the most common secondary structural elements seen in membrane proteins and are packed in the form of helix bundles. These -helices encounter varying external environments (hydrophobic, hydrophilic) that may influence the sequence preferences at their N and C-termini. The role of the external environment in stabilization of the helix termini in membrane proteins is still unknown. Here we analyze -helices in a high-resolution dataset of integral -helical membrane proteins and establish that their sequence and conformational preferences differ from those in globular proteins. We specifically examine these preferences at the N and C-termini in helices initiating/terminating inside the membrane core as well as in linkers connecting these transmembrane helices. We find that the sequence preferences and structural motifs at capping (Ncap and Ccap) and near-helical (N' and C') positions are influenced by a combination of features including the membrane environment and the innate helix initiation and termination property of residues forming structural motifs. We also find that a large number of helix termini which do not form any particular capping motif are stabilized by formation of hydrogen bonds and hydrophobic interactions contributed from the neighboring helices in the membrane protein. We further validate the sequence preferences obtained from our analysis with data from an ultradeep sequencing study that identifies evolutionarily conserved amino acids in the rat neurotensin receptor. The results from our analysis provide insights for the secondary structure prediction, modeling and design of membrane proteins. Proteins 2014; 82:3420-3436. (c) 2014 Wiley Periodicals, Inc.

Directing peptide conformation with centrally positioned pre-organized dipeptide segments: studies of a 12-residue helix and beta-hairpin

Secondary structure formation in oligopeptides can be induced by short nucleating segments with a high propensity to form hydrogen bonded turn conformations. Type I/III turns facilitate helical folding while type II'/I' turns favour hairpin formation. This principle is experimentally verified by studies of two designed dodecapeptides, Boc-Val-Phe-Leu-Phe-Val-Aib-Aib-Val-Phe-Leu-Phe-Val-OMe 1 and Boc-Val-Phe-Leu-Phe-Val- (D) Pro- (L) Pro-Val-Phe-Leu-Phe-Val-OMe 2. The N- and C-terminal flanking pentapeptide sequences in both cases are identical. Peptide 1 adopts a largely alpha-helical conformation in crystals, with a small 3(10) helical segment at the N-terminus. The overall helical fold is maintained in methanol solution as evidenced by NMR studies. Peptide 2 adopts an antiparallel beta-hairpin conformation stabilized by 6 interstrand hydrogen bonds. Key nuclear Overhauser effects (NOEs) provide evidence for the antiparallel beta-hairpin structure. Aromatic proton chemical shifts provide a clear distinction between the conformation of peptides 1 (helical) and 2 (beta-hairpin). The proximity of facing aromatic residues positioned at non-hydrogen bonding positions in the hairpin results in extensively ring current shifted proton resonances in peptide 2.

Performance Analysis of Space-Shift Keying in Decode-and-Forward Multihop MIMO Networks

In this paper, space-shift keying (SSK) is considered for multihop multiple-input-multiple-output (MIMO) networks. In SSK, only one among n(s) = 2(m) available transmit antennas, chosen on the basis of m information bits, is activated during transmission. We consider two different systems of multihop co-operation, where each node has multiple antennas and employs SSK. In system I, a multihop diversity relaying scheme is considered. In system II, a multihop multibranch relaying scheme is considered. In both systems, we adopt decode-and-forward (DF) relaying, where each relay forwards the signal only when it correctly decodes. We analyze the end-to-end bit error rate (BER) and diversity order of both the systems with SSK. For binary SSK (n(s) = 2), our analytical BER expression is exact, and our numerical results show that the BERs evaluated through the analytical expression overlap with those obtained through Monte Carlo simulations. For nonbinary SSK (n(s) > 2), we derive an approximate BER expression, where the analytically evaluated BER results closely follow the simulated BER results. We show the comparison of the BERs of SSK and conventional phase-shift keying (PSK) and also show the instances where SSK outperforms PSK. We also present the diversity analyses for SSK in systems I and II, which predict the achievable diversity orders as a function of system parameters.

Space-Time Coded Spatial Modulated Physical Layer Network Coding for Two-Way Relaying

Using the spatial modulation approach, where only one transmit antenna is active at a time, we propose two transmission schemes for two-way relay channel using physical layer network coding with space time coding using coordinate interleaved orthogonal designs (CIODs). It is shown that using two uncorrelated transmit antennas at the nodes, but using only one RF transmit chain and space-time coding across these antennas can give a better performance without using any extra resources and without increasing the hardware implementation cost and complexity. In the first transmission scheme, two antennas are used only at the relay, adaptive network coding (ANC) is employed at the relay and the relay transmits a CIOD space time block code (STBC). This gives a better performance compared to an existing ANC scheme for two-way relay channel which uses one antenna each at all the three nodes. It is shown that for this scheme at high SNR the average end-to-end symbol error probability (SEP) is upper bounded by twice the SEP of a point-to-point fading channel. In the second transmission scheme, two transmit antennas are used at all the three nodes, CIOD STBCs are transmitted in multiple access and broadcast phases. This scheme provides a diversity order of two for the average end-to-end SEP with an increased decoding complexity of O(M-3) for an arbitrary signal set and O(M-2 root M) for square QAM signal set. Simulation results show that the proposed schemes performs better than the existing ANC schemes under perfect and imperfect channel state information.

Large-Scale Multiuser SM-MIMO Versus Massive MIMO

Spatial modulation (SM) is attractive for multiantenna wireless communications. SM uses multiple transmit antenna elements but only one transmit radio frequency (RF) chain. In SM, in addition to the information bits conveyed through conventional modulation symbols (e.g., QAM), the index of the active transmit antenna also conveys information bits. In this paper, we establish that SM has significant signal-to-noise (SNR) advantage over conventional modulation in large-scale multiuser (multiple-input multiple-output) MIMO systems. Our new contribution in this paper addresses the key issue of large-dimension signal processing at the base station (BS) receiver (e.g., signal detection) in large-scale multiuser SM-MIMO systems, where each user is equipped with multiple transmit antennas (e.g., 2 or 4 antennas) but only one transmit RF chain, and the BS is equipped with tens to hundreds of (e.g., 128) receive antennas. Specifically, we propose two novel algorithms for detection of large-scale SM-MIMO signals at the BS; one is based on message passing and the other is based on local search. The proposed algorithms achieve very good performance and scale well. For the same spectral efficiency, multiuser SM-MIMO outperforms conventional multiuser MIMO (recently being referred to as massive MIMO) by several dBs. The SNR advantage of SM-MIMO over massive MIMO can be attributed to: (i) because of the spatial index bits, SM-MIMO can use a lower-order QAM alphabet compared to that in massive MIMO to achieve the same spectral efficiency, and (ii) for the same spectral efficiency and QAM size, massive MIMO will need more spatial streams per user which leads to increased spatial interference.

Identification of local variations within secondary structures of proteins

Secondary-structure elements (SSEs) play an important role in the folding of proteins. Identification of SSEs in proteins is a common problem in structural biology. A new method, ASSP (Assignment of Secondary Structure in Proteins), using only the path traversed by the C atoms has been developed. The algorithm is based on the premise that the protein structure can be divided into continuous or uniform stretches, which can be defined in terms of helical parameters, and depending on their values the stretches can be classified into different SSEs, namely -helices, 3(10)-helices, -helices, extended -strands and polyproline II (PPII) and other left-handed helices. The methodology was validated using an unbiased clustering of these parameters for a protein data set consisting of 1008 protein chains, which suggested that there are seven well defined clusters associated with different SSEs. Apart from -helices and extended -strands, 3(10)-helices and -helices were also found to occur in substantial numbers. ASSP was able to discriminate non--helical segments from flanking -helices, which were often identified as part of -helices by other algorithms. ASSP can also lead to the identification of novel SSEs. It is believed that ASSP could provide a better understanding of the finer nuances of protein secondary structure and could make an important contribution to the better understanding of comparatively less frequently occurring structural motifs. At the same time, it can contribute to the identification of novel SSEs. A standalone version of the program for the Linux as well as the Windows operating systems is freely downloadable and a web-server version is also available at .

Calcium binding properties of calcium dependent protein kinase 1 (CaCDPK1) from Cicer arietinum

Calcium plays a crucial role as a secondary messenger in all aspects of plant growth, development and survival. Calcium dependent protein kinases (CDPKs) are the major calcium decoders, which couple the changes in calcium level to an appropriate physiological response. The mechanism by which calcium regulates CDPK protein is not well understood. In this study, we investigated the interactions of Ca2+ ions with the CDPK1 isoform of Cicer arietinum (CaCDPK1) using a combination of biophysical tools. CaCDPK1 has four different EF hands as predicted by protein sequence analysis. The fluorescence emission spectrum of CaCDPK1 showed quenching with a 5 nm red shift upon addition of calcium, indicating conformational changes in the tertiary structure. The plot of changes in intensity against calcium concentrations showed a biphasic curve with binding constants of 1.29 mu M and 120 mu M indicating two kinds of binding sites. Isothermal calorimetric (ITC) titration with CaCl2 also showed a biphasic curve with two binding constants of 0.027 mu M and 1.7 mu M. Circular dichroism (CD) spectra showed two prominent peaks at 208 and 222 nm indicating that CaCDPK1 is a alpha-helical rich protein. Calcium binding further increased the alpha-helical content of CaCDPK1 from 75 to 81%. Addition of calcium to CaCDPK1 also increased fluorescence of 8-anilinonaphthalene-1-sulfonic acid (ANS) indicating exposure of hydrophobic surfaces. Thus, on the whole this study provides evidence for calcium induced conformational changes, exposure of hydrophobic surfaces and heterogeneity of EF hands in CaCDPK1. (C) 2015 Elsevier GmbH. All rights reserved.

Structural characterization of folded and extended conformations in peptides containing gamma amino acids with proteinogenic side chains: crystal structures of gamma(n), (alpha gamma)(n) and gamma gamma delta gamma sequences

The crystal structures of nine peptides containing gamma(4)Val and gamma(4)Leu are described. The short sequences Boc-gamma(4)(R)Val](2)-OMe 1, Boc-gamma(4)(R)Val](3)-NHMe 2 and Boc-gamma(4)(S)Val-gamma(4)(R)Val-OMe 3 adopt extended apolar, sheet like structures. The tetrapeptide Boc-gamma(4)(R)Val](4)-OMe 4 adopts an extended conformation, in contrast to the folded C-14 helical structure determined previously for Boc-gamma(4)(R)Leu](4)-OMe. The hybrid alpha gamma sequence Boc-Ala-gamma(4)(R)Leu](2)-OMe 5 adopts an S-shaped structure devoid of intramolecular hydrogen bonds, with both alpha residues adopting local helical conformations. In sharp contrast, the tetrapeptides Boc-Aib-gamma(4)(S)Leu](2)-OMe 6 and Boc-Leu-gamma(4)(R)Leu](2)-OMe 7 adopt folded structures stabilized by two successive C-12 hydrogen bonds. gamma(4)Val residues have also been incorporated into the strand segments of a crystalline octapeptide, Boc-Leu-gamma(4)(R)Val-Val-(D)Pro-Gly-Leu-gamma(4)(R)Val-Val-OMe 8. The gamma gamma delta gamma tetrapeptide containing gamma(4)Val and delta(5)Leu residues adopts an extended sheet like structure. The hydrogen bonding pattern at gamma residues corresponds to an apolar sheet, while a polar sheet is observed at the lone delta residue. The transition between folded and extended structures at gamma residues involves a change of the torsion angle from the gauche to the trans conformation about the C-beta-C-alpha bond.

Independent Positioning of Magnetic Nanomotors

There is considerable interest in powering and maneuvering nanostructures remotely in fluidic media using noninvasive fuel-free methods, for which small homogeneous magnetic fields are ideally suited. Current strategies include helical propulsion of chiral nanostructures, cilia-like motion of flexible filaments, and surface assisted translation of asymmetric colloidal doublets and magnetic nanorods, in all of which the individual structures are moved in a particular direction that is completely tied to the characteristics of the driving fields. As we show in this paper, when we use appropriate magnetic field configurations and actuation time scales, it is possible to maneuver geometrically identical nanostructures in different directions, and subsequently position them at arbitrary locations with respect to each other. The method reported here requires proximity of the nanomotors to a solid surface, and could be useful in applications that require remote and independent control over individual components in microfluidic environments.

NUMERICAL STUDIES OF DYNAMO ACTION IN A TURBULENT SHEAR FLOW. I.

We perform numerical experiments to study the shear dynamo problem where we look for the growth of a large-scale magnetic field due to non-helical stirring at small scales in a background linear shear flow in previously unexplored parameter regimes. We demonstrate the large-scale dynamo action in the limit where the fluid Reynolds number (Re) is below unity while the magnetic Reynolds number (Rm) is above unity; the exponential growth rate scales linearly with shear, which is consistent with earlier numerical works. The limit of low Re is particularly interesting, as seeing the dynamo action in this limit would provide enough motivation for further theoretical investigations, which may focus attention on this analytically more tractable limit of Re < 1 compared to the more formidable limit of Re > 1. We also perform simulations in the regimes where (i) both (Re, Rm) < 1, and (ii) Re > 1 and Rm < 1, and compute all of the components of the turbulent transport coefficients (alpha(ij) and alpha(ij)) using the test-field method. A reasonably good agreement is observed between our results and the results of earlier analytical works in similar parameter regimes.

Generalized Spatial Modulation in Large-Scale Multiuser MIMO Systems

Generalized spatial modulation (GSM) uses n(t) transmit antenna elements but fewer transmit radio frequency (RF) chains, n(rf). Spatial modulation (SM) and spatial multiplexing are special cases of GSM with n(rf) = 1 and n(rf) = n(t), respectively. In GSM, in addition to conveying information bits through n(rf) conventional modulation symbols (for example, QAM), the indices of the n(rf) active transmit antennas also convey information bits. In this paper, we investigate GSM for large-scale multiuser MIMO communications on the uplink. Our contributions in this paper include: 1) an average bit error probability (ABEP) analysis for maximum-likelihood detection in multiuser GSM-MIMO on the uplink, where we derive an upper bound on the ABEP, and 2) low-complexity algorithms for GSM-MIMO signal detection and channel estimation at the base station receiver based on message passing. The analytical upper bounds on the ABEP are found to be tight at moderate to high signal-to-noise ratios (SNR). The proposed receiver algorithms are found to scale very well in complexity while achieving near-optimal performance in large dimensions. Simulation results show that, for the same spectral efficiency, multiuser GSM-MIMO can outperform multiuser SM-MIMO as well as conventional multiuser MIMO, by about 2 to 9 dB at a bit error rate of 10(-3). Such SNR gains in GSM-MIMO compared to SM-MIMO and conventional MIMO can be attributed to the fact that, because of a larger number of spatial index bits, GSM-MIMO can use a lower-order QAM alphabet which is more power efficient.

Inner Bound on the GDOF of the K-User MIMO Gaussian Symmetric Interference Channel

The K-user multiple input multiple output (MIMO) Gaussian symmetric interference channel where each transmitter has M antennas and each receiver has N antennas is studied from a generalized degrees of freedom (GDOF) perspective. An inner bound on the GDOF is derived using a combination of techniques such as treating interference as noise, zero forcing (ZF) at the receivers, interference alignment (IA), and extending the Han-Kobayashi (HK) scheme to K users, as a function of the number of antennas and the log INR/log SNR level. Several interesting conclusions are drawn from the derived bounds. It is shown that when K > N/M + 1, a combination of the HK and IA schemes performs the best among the schemes considered. When N/M < K <= N/M + 1, the HK-scheme outperforms other schemes and is found to be GDOF optimal in many cases. In addition, when the SNR and INR are at the same level, ZF-receiving and the HK-scheme have the same GDOF performance.

Outer Bounds on the Sum Rate of the K-User MIMO Gaussian Interference Channel

This paper derives outer bounds on the sum rate of the K-user MIMO Gaussian interference channel (GIC). Three outer bounds are derived, under different assumptions of cooperation and providing side information to receivers. The novelty in the derivation lies in the careful selection of side information, which results in the cancellation of the negative differential entropy terms containing signal components, leading to a tractable outer bound. The overall outer bound is obtained by taking the minimum of the three outer bounds. The derived bounds are simplified for the MIMO Gaussian symmetric IC to obtain outer bounds on the generalized degrees of freedom (GDOF). The relative performance of the bounds yields insight into the performance limits of multiuser MIMO GICs and the relative merits of different schemes for interference management. These insights are confirmed by establishing the optimality of the bounds in specific cases using an inner bound on the GDOF derived by the authors in a previous work. It is also shown that many of the existing results on the GDOF of the GIC can be obtained as special cases of the bounds, e. g., by setting K = 2 or the number of antennas at each user to 1.