Mechanism for the alpha-helix to beta-hairpin transition

The aggregation of alpha-helix-rich proteins into beta-sheet-rich amyloid fibrils is associated with fatal diseases, such as Alzheimer's disease and prion disease. During an aggregation process, protein secondary structure elements-alpha-helices-undergo conformational changes to beta-sheets. The fact that proteins with different sequences and structures undergo a similar transition on aggregation suggests that the sequence nonspecific hydrogen bond interaction among protein backbones is an important factor. We perform molecular dynamics simulations of a polyalanine model, which is an alpha-helix in its native state and observe a metastable beta-hairpin intermediate. Although a beta-hairpin has larger potential energy than an alpha-helix, the entropy of a beta-hairpin is larger because of fewer constraints imposed by the hydrogen bonds. In the vicinity of the transition temperature, we observe the interconversion of the alpha-helix and beta-sheet states via a random coil state. We also study the effect of the environment by varying the relative strength of side-chain interactions for a designed peptide-an alpha-helix in its native state. For a certain range of side-chain interaction strengths, we find that the intermediate beta-hairpin state is destabilized and even disappears, suggesting an important role of the environment in the aggregation propensity of a peptide.     

Understanding the folding and stability of a zinc finger-based full sequence design protein with replica exchange molecular dynamics simulations

Full sequence design protein FSD-1 is a designed protein based on the motif of zinc finger protein. In this work, its folding mechanism and thermal stability are investigated using the replica exchange molecular dynamics model with the water molecules being treated explicitly. The results show that the folding of the FSD-1 is initiated by the hydrophobic collapse, which is accompanied with the formation of the C-terminal alpha-helix. Then the folding proceeds with the formation of the beta-hairpin and the further package of the hydrophobic core. Compared with the beta-hairpin, the alpha-helix has much higher stability. It is also found that the N-capping motif adopted by the FSD-1 contributes to the stability of the alpha-helix dramatically. The hydrophobic contacts made by the side chain of Tyr3 in the native state are essential for the stabilization of the beta-hairpin. It is also found that the folding of the N-terminal beta-hairpin and the C-terminal alpha-helix exhibits weak cooperativity, which is consistent with the experimental data. Meanwhile, the folding pathway is compared between the FSD-1 and the target zinc finger peptide, and the possible role of the zinc ion on the folding pathway of zinc finger is proposed. Proteins 2007. (c) 2007 Wiley-Liss, Inc.     

Heterogeneous folding of the trpzip hairpin: full atom simulation and experiment

The beta-hairpin trpzip2 can be tuned continuously from a two-state folder to folding on a rough energy landscape without a dominant refolding barrier. At high denaturant concentration, this extremely stable peptide exhibits a single apparent "two-state" transition temperature when monitored by different spectroscopic techniques. However, under optimal folding conditions the hairpin undergoes an unusual folding process with three clusters of melting transitions ranging from 15 degrees C to 160 degrees C, as monitored by 12 different experimental and computational observables. We explain this behavior in terms of a rough free energy landscape of the unfolded peptide caused by multiple tryptophan interactions and alternative backbone conformations. The landscape is mapped out by potentials of mean force derived from replica-exchange molecular dynamics simulations. Implications for deducing cooperativity from denaturant titrations, for the origin of folding cooperativity, and for the folding of thermophilic proteins are pointed out. trpzip is an excellent small tunable model system for the glass-like folding transitions predicted by landscape theory.     

A Unified Poland-Scheraga Model of Oligo- and Polynucleotide DNA Melting: Salt Effects and Predictive Power

Key biological and nano-technological processes require the partial or complete association and dissociation of complementary DNA strands. We present a variant of the Poland-Scheraga model for DNA melting where we introduce a local, sequence-dependent salt correction of the nearest-neighbor parameters. Furthermore, our formulation accounts for capping and interfacial energies of helical and coiled chain sections. We show that the model reproduces experimental data for melting temperatures over the full experimental range of strand length, strand concentration, and ionic strength of the solution. In particular, we reproduce a phenomenological relation by Frank-Kamenetskii for very long chains using a parameterization based on melting curves for short oligomers. However, we also show that the parameters of the Poland-Scheraga model are still not known with sufficient precision to quantitatively predict the fine structure of melting curves. This formulation of the Poland-Scheraga model opens the possibility to overcome this limitation by optimizing parameters with respect to an extended base of experimental data for short-, medium-, and long-chain melting. We argue that the often-discarded melting data for longer oligomers exhibiting non-two-state transitions could play a particularly important role.     

Studies of DNA dumbbells. VI. Analysis of optical melting curves of dumbbells with a sixteen-base pair duplex stem and end-loops of variable size and sequence

Optical melting curves of 22 DNA dumbbells with the 16-base pair duplex sequence 5′-G-C-A-T-C-A-T-C-G-A-T-G-A-T-G-C-3′ linked on both ends by single-strand loops of A_t or C_t sequences (˛ = 2, 3, 4, 6, 8, 10, 14), T_t sequences (˛ = 2, 3, 4, 6, 8, 10), and G_t sequences (t = 2, 4) were measured in phosphate buffered solvents containing 30, 70, and 120 mM Na⁺. For dumbbells with loops comprised of at least three nucleotides, stability is inversely proportional to end-loop size. Dumbbells with loops comprised of only two nucleotide bases generally have lower stabilities than dumbbells with three base nucleotide loops. Experimental melting curves were analyzed in terms of the numerically exact (multistate) statistical thermodynamic model of DNA dumbbell melting previously described (T. M. Paner, M. Amaratunga & A. S. Benight (1992), Biopolymers 32, 881). Theoretically calculated melting curves were fitted to experimental curves by simultaneously adjusting model parameters representing statistical weights of intramolecular hairpin loop and single-strand circle states. The systematically determined empirical parameters provided evaluations of the energetics of hairpin loop formation as a function of loop size, sequence, and salt environment. Values of the free energies of hairpin loop formation ΔG_loop(n > t) and single-strand circles, ΔG_cir(N) as a function of end-loop size, t = 2-14, circle size, N = 32 + 2_t, and loop sequence were obtained. These quantities were found to depend on end-loop size but not loop sequence. Their empirically determined values also varied with solvent ionic strength. Analytical expressions for the partition function Q(T) of the dumbbells were evaluated using the empirically evaluated best-fit loop parameters. From Q(T), the melting transition enthalpy ΔH, entropy ΔS, and free energy ΔG, were evaluated for the dumbbells as a function of end-loop size, sequence, and [Na⁺]. Since the multistate analysis is based on the numerically exact model, and considers a statistically significant number of theoretically possible partially melted states, it does not require prior assumptions regarding the nature of the melting transition, i.e., whether or not it occurs in a two-state manner. For comparison with the multistate analysis, thermodynamic transition parameters were also evaluated directly from experimental melting curves assuming a two-state transition and using the graphical van't Hoff analysis. Comparisons between results of the multistate and two-state analyses suggested dumbbells with loops comprised of six or fewer residues melted in a two-state manner, while the melting processes for dumbbells with larger end-loops deviate from two-state behavior.Dependence of thermodynamic parameters on[Na⁺] as a function of loop size suggests single-strand end-loops have different counterion binding properties than the melted circle. Results are compared with those obtained in an earlier study of dumbbells with the slightly different stem sequence 5'-G-C-A-T-A-G-A-T-G-A-G-A-A-T-G-C-3' linked on the ends by T loops (˛ = 2,3,4,6,8,10,14).© 1996 John Wiley &Sons, Inc.     

Thermodynamic stability of the 5' dangling-ended DNA hairpins formed from sequences 5'-(XY)2GGATAC(T)4GTATCC-3', where X, Y = A, T, G, C

Expressions for the partition function Q (T) of DNA hairpins are presented. Calculations of Q (T), in conjunction with our previously reported numerically exact algorithm [T. M. Paner, M. Amaratunga, M. J. Doktycz, and A. S. Benight (1990) Biopolymers, 29, 1715-1734], yield a numerical method to evaluate the temperature dependence of the transition enthalpy, entropy, and free energy of a DNA hairpin directly from its optical melting curve. No prior assumptions that the short hairpins melt in a two-state manner are required. This method is then applied in a systematic manner to investigate the stability of the six basepair duplex stem 5'-GGATAC-3' having four-base dangling single-strand ends with the sequences (XY)2, where X, Y = A, T, G, C, on the 5' end and a T4 loop on the 3' end. Results show that all dangling ends of the sample set stabilize the hairpin against melting. Increases in transition temperatures as great as 4.0 degrees C above the blunt-ended control hairpin were observed. The hierarchy of the hairpin transition temperatures is dictated by the identity of the first base of the dangling end adjoining the duplex in the order: purine greater than T greater than C. Calculated melting curves of every hairpin were fit to experimental curves by adjustment of a single parameter in the numerically exact theoretical algorithm. Exact fits were obtained in all cases. Experimental melting curves were also calculated assuming a two-state melting process. Equally accurate fits of all dangling-ended hairpin melting curves were obtained with the two-state model calculation. This was not the case for the melting curve of the blunt-ended hairpin, indicating the presence of a four-base dangling-end drives hairpin melting to a two-state process. Q (T) was calculated as a function of temperature for each hairpin using the theoretical parameters that provided calculated curves in exact agreement with the experimentally obtained optical melting curves. From Q (T), the temperature dependence of the transition enthalpy delta H, entropy delta S, and free energy delta G were calculated for every hairpin providing a quantitative assessment of the effects of dangling ends on hairpin thermodynamics. Comparisons of our results are made with those of the Breslauer group [M. Senior, R. A. Jones, and K. J. Breslauer (1988) Biochemistry 27, 3879-3885] on the T2 5' dangling-ended d(GC)3 duplexes.(ABSTRACT TRUNCATED AT 400 WORDS)     

Calorimetric study of the order-disorder conformational transition in succinoglycan

Thermally induced order-disorder conformational transition in succinoglycan was studied using the method of high-sensitivity differential scanning microcalorimetry within the range of polysaccharide concentrations from 0.1 to 3.5 mg mL⁻¹ at NaCl concentrations 0, 0.01, and 0.1M. The positions and shapes of the excess heat capacity curves depended substantially on both the NaCl and polysaccharide concentrations. At low polysaccharide concentrations in salt-free solution the experimental curves were closely approximated by the two-state model suggesting the transition mechanism to be of the single helix-coil type. With increasing polysaccharide and/or NaCl concentration, the experimental curves changed significantly in symmetry, which indicated a changing transition mechanism. At high polysaccharide concentrations or in the presence of the salt, the order-disorder transition of succinoglycan was shown to include two stages: the cooperative dissociation of the helix dimer and subsequent two-state melting of the helix monomer. The dependence of thermodynamic parameters for the dissociation and melting of helix structures in succinoglycan on NaCl and polysaccharide concentrations was obtained by fitting the experimental excess heat capacity curves. The cooperativity parameter σ for the single helix-coil transition as well as the average length of the helix segment of succinoglycan were calculated. Some features of succinoglycan ordering in solution are discussed. © 1996 John Wiley & Sons, Inc.     

Protein engineering study of protein L by simulation.

We examine the ability of our recently introduced minimalist protein model to reproduce experimentally measured thermodynamic and kinetic changes upon sequence mutation in the well-studied immunoglobulin-binding protein L. We have examined five different sequence mutations of protein L that are meant to mimic the same mutation type studied experimentally: two different mutations which disrupt the natural preference in the beta-hairpin #1 and beta-hairpin #2 turn regions, two different helix mutants where a surface polar residue in the alpha-helix has been mutated to a hydrophobic residue, and a final mutant to further probe the role of nonnative hydrophobic interactions in the folding process. These simulated mutations are analyzed in terms of various kinetic and thermodynamic changes with respect to wild type, but in addition we evaluate the structure-activity relationship of our model protein based on the phi-value calculated from both the kinetic and thermodynamic perspectives. We find that the simulated thermodynamic phi-values reproduce the experimental trends in the mutations studied and allow us to circumvent the difficult interpretation of the complicated kinetics of our model. Furthermore, the level of resolution of the model allows us to directly predict what experiments seek in regard to protein engineering studies of protein folding--namely the residues or portions of the polypeptide chain that contribute to the crucial step in the folding of the wild-type protein.     

Free energy surfaces of beta-hairpin and alpha-helical peptides generated by replica exchange molecular dynamics with the AGBNP implicit solvent model

We have studied the potential of mean force of two peptides, one known to adopt a beta-hairpin and the other an alpha-helical conformation in solution. These peptides are, respectively, residues 41-56 of the C-terminus (GEWTYDDATKTFTVTE) of the B1 domain of protein G and the 13 residue C-peptide (KETAAAKFERQHM) of ribonuclease A. Extensive canonical ensemble sampling has been performed using a parallel replica exchange method. The effective potential employed in this work consists of the OPLS all-atom force field (OPLS-AA) and an analytical generalized Born (AGB) implicit solvent model including a novel nonpolar solvation free energy estimator (NP). An additional dielectric screening parameter has been incorporated into the AGBNP model. In the case of the beta-hairpin, the nonpolar solvation free energy estimator provides the necessary effective interactions for the collapse of the hydrophobic core (W43, Y45, F52, and V54), which the more commonly used surface-area-dependent nonpolar model does not provide. For both the beta-hairpin and the alpha-helix, increased dielectric screening reduces the stability of incorrectly formed salt bridges, which tend to disrupt the formation of the hairpin and helix, respectively. The fraction of beta-hairpin and alpha-helix content we obtained using the AGBNP model agrees well with experimental results. The thermodynamic stability of the beta-hairpin from protein G and the alpha-helical C-peptide from ribonuclease A as modeled with the OPLS-AA/AGBNP effective potential reflects the balance between the nonpolar effective potential terms, which drive compaction, and the polar and hydrogen bonding terms, which promote secondary structure formation.     

Simulation of alpha-helix and beta-hairpin formation in water-soluble proteins by the code physics method

One of the possible ways for complete and final solution of the problem of determination of three-dimensional structure of proteins on amino acid sequence is simulation of protein three-dimensional structure formation. The use of the code physics method developed by the author has been suggested to fulfill this task. The simulation of alpha-helix and beta-hairpin formation in water-soluble proteins as a start of realization of the plan is described here. The results of the simulation were compared with the experimental data for 14 proteins of no more than 50 amino acids and therefore with little number of alpha-helices and beta-strands (to meet limits of simulation process) and with secondary structure predictions by the best to data methods of protein secondary structure prediction, PSIpred, PORTER and PROFsec. Secondary structure of the proteins, obtained as a result of the simulation of alpha-helix and beta-hairpin formation using the code physics method, corresponded completely to experimental data while the secondary structure predicted by the PSIpred, PORTER and PROFsec methods differed from these data significantly.     

Prediction of folding transition-state position (betaT) of small, two-state proteins from local secondary structure content

Folding kinetics of proteins is governed by the free energy and position of transition states. But attempts to predict the position of folding transition state on reaction pathway from protein structure have been met with only limited success, unlike the folding-rate prediction. Here, we find that the folding transition-state position is related to the secondary structure content of native two-state proteins. We present a simple method for predicting the transition-state position from their alpha-helix, turn and polyproline secondary structures. The method achieves 81% correlation with experiment over 24 small, two-state proteins, suggesting that the local secondary structure content, especially for content of alpha-helix, is a determinant of the solvent accessibility of the transition state ensemble and size of folding nucleus.     

Thermodynamic differences among homologous thermophilic and mesophilic proteins.

Here, we analyze the thermodynamic parameters and their correlations in families containing homologous thermophilic and mesophilic proteins which show reversible two-state folding <--> unfolding transitions between the native and the denatured states. For the proteins in these families, the melting temperatures correlate with the maximal protein stability change (between the native and the denatured states) as well as with the enthalpic and entropic changes at the melting temperature. In contrast, the heat capacity change is uncorrelated with the melting temperature. These and additional results illustrate that higher melting temperatures are largely obtained via an upshift and broadening of the protein stability curves. Both thermophilic and mesophilic proteins are maximally stable around room temperature. However, the maximal stabilities of thermophilic proteins are considerably greater than those of their mesophilic homologues. At the living temperatures of their respective source organisms, homologous thermophilic and mesophilic proteins have similar stabilities. The protein stability at the living temperature of the source organism does not correlate with the living temperature of the protein. We tie thermodynamic observations to microscopics via the hydrophobic effect and a two-state model of the water structure. We conclude that, to achieve higher stability and greater resistance to high and low temperatures, specific interactions, particularly electrostatic, should be engineered into the protein. The effect of these specific interactions is largely reflected in an increased enthalpy change at the melting temperature.     

Studies of DNA dumbbells. III. Theoretical analysis of optical melting curves of dumbbells with a 16 base-pair duplex stem and Tn end loops (n = 2, 3, 4, 6, 8, 10, 14).

Optical melting curves of seven DNA dumbbells with the 16 base-pair duplex sequence 5'G-C-A-T-A-G-A-T-G-A-G-A-A-T-G-C3' linked on both ends by Tn (n = 2, 3, 4, 6, 8, 10, and 14) loops measured in 30, 70, and 120 mM Na+ are analyzed in terms of the numerically exact statistical thermodynamic model of DNA melting. The construction and characterization of these molecules were described in the previous paper (Amaratunga et al., 1992). As was recently reported for hairpins (T. M. Paner, M. Amaratunga, M. J. Doktycz, and A. S. Benight, 1990, Biopolymers, Vol. 29, pp. 1715-1734) theoretically calculated melting curves were fitted to experimental curves by simultaneously adjusting the parameters representing loop and circle formation to optimize the fits. The systematically determined empirical parameters provide evaluations of the free energies of hairpin loop formation delta Gloop (n) and single-strand circles delta Gcircle (N), as a function of end loop size, n = 2-14, and circle size, N = 32 + 2n. The dependence of these quantities on solvent ionic strength over the range from 30 to 120 mM Na+ was evaluated. An approximately analytical expression for the partition function Q(T) of the dumbbells was formulated that allowed a means for determining the transition enthalpy delta H degrees and entropy delta S degrees for every dumbbell, revealing the dependence of these quantities on loop size. In this multistate approach a manifold of partially melted intermediate microstates are considered and therefore no assumptions regarding the nature of the melting transitions (that they are two-state) are required. The transition thermodynamic parameters were also determined from a van't Hoff analysis of the melting curves. Comparisons between the results of the multistate analysis and the two-state van't Hoff analysis revealed significant differences for the dumbbells with larger end loops, indicating that the melting transitions of the larger looped dumbbells deviate considerably from two-state behavior. Results are then compared with published melting studies of much larger DNA dumbbells (D. B. Naritsin and Y. L. Lyubchenko, 1990, Journal of Biomolecular Structure and Dynamics, Vol. 8, pp. 1-13), of small hairpins (Paner et al., 1990; M. J. Doktycz, T. M. Paner, M. Amaratunga and A. S. Benight, 1990, Biopolymers, Vol. 30, pp. 829-845) and another dumbbell (A. S. Benight, J. M. Schurr, P. F. Flynn, B. R. Reid, and D. E. Wemmer, 1988) Journal of Molecular Biology, Vol. 200, pp. 377-399).(ABSTRACT TRUNCATED AT 400 WORDS)     

Two-state folding over a weak free-energy barrier

We present a Monte Carlo study of a model protein with 54 amino acids that folds directly to its native three-helix-bundle state without forming any well-defined intermediate state. The free-energy barrier separating the native and unfolded states of this protein is found to be weak, even at the folding temperature. Nevertheless, we find that melting curves to a good approximation can be described in terms of a simple two-state system, and that the relaxation behavior is close to single exponential. The motion along individual reaction coordinates is roughly diffusive on timescales beyond the reconfiguration time for a single helix. A simple estimate based on diffusion in a square-well potential predicts the relaxation time within a factor of two.     

The nature of stacking equilibria in polynucleotides

Temperature melting profiles of adenylyladenosine and cytidylylcytidine were examined by ultraviolet absorption, circular dichroism, and optical rotatory dispersion. They showed the following characteristics: profiles for different absorption wavelengths are identical as defined by least-squares computed optical and thermodynamic parameters; melting curves obtained by the three spectroscopic methods are likewise in all cases identical by a series of criteria; in terms of the operational equilibrium constant for base-stacking all van't Hoff plots are linear; absorption spectra and circular dichroism curves at a series of temperatures for both dinucleoside phosphates give excellent isosbestic points; a matrix-rank analysis of the family of complete spectra at different temperatures gives a value of two for the numbers of components in both cases. Four criteria are thus fulfilled of a two-state system for the stacking equilibrium. The results are not compatible with a multi-state scheme in which the substates are optically distinguishable. There is no measurable effect of ionic strength up to 1.0. In a presence of high concentrations of lithium chloride the criteria for two-state behavior are no longer fulfilled, and examination of infrared spectra gives evidence of complex formation by this salt, though not by sodium chloride. A destacking profile, similar to that observed on heating, is obtained by progressive addition of ethylene glycol to the solution. It is suggested that in dimers, though not in higher oligomers or polymers, the stacking equilibrium can be operationally regarded as a two-state system, and that the meaningful thermodynamic parameters can be extracted by analytical treatment, of the type here developed, of the melting profiles.     

Thermal folding and mechanical unfolding pathways of protein secondary structures

Mechanical stretching of secondary structures is studied through molecular dynamics simulations of a Go-like model. Force versus displacement curves are studied as a function of the stiffness and velocity of the pulling device. The succession of stretching events, as measured by the order in which contacts are ruptured, is compared to the sequencing of events during thermal folding and unfolding. Opposite cross-correlations are found for an alpha-helix and a beta-hairpin structure. In a tandem of two alpha-helices, the two constituent helices unravel nearly simultaneously. A simple condition for simultaneous versus sequential unraveling of repeat units is presented.     

All-atom replica exchange molecular simulation of protein BBL

Downhill folding is one of the most important predictions of energy landscape theory. Recently, the Escherichia coli 2-oxoglutarate dehydrogenase PSBD was described as a first example of global downhill folding (Garcia-Mira et al., Science 2002;298:2191), classification that has been later subject of significant controversy. To help resolve this problem, by using intensive all-atom simulation with explicit water model and the replica exchange method, we sample the phase space of protein BBL and depict the free energy landscape. We give an estimate of the free energy barrier height of 1-2 k(B)T, dependent on the way the energy landscape is projected. We also study the conformational distribution of the transition region and find that the three helices generally take the similar positions as that in the native states whereas their spatial orientations show large variability. We further detect the inconsistency between different signals by individually fitting the thermal denaturation curves of five structural features using two-state model, which gives a wide spread melting temperature of 19 K. All of these features are consistent with a picture of folding with very low cooperativities. Compared with the experimental data (Sadqi et al., Nature 2006; 442:317), our results indicate that the Naf-BBL (pH5.3) may have an even lower barrier height and cooperativity.     

Nanosecond temperature jump relaxation dynamics of cyclic beta-hairpin peptides

The thermal unfolding of a series of 6-, 10-, and 14-mer cyclic beta-hairpin peptides was studied to gain insight into the mechanism of formation of this important secondary structure. The thermodynamics of the transition were characterized using temperature dependent Fourier transform infrared spectroscopy. Thermodynamic data were analyzed using a two-state model which indicates increasing cooperativity along the series. The relaxation kinetics of the peptides in response to a laser induced temperature jump were probed using time-resolved infrared spectroscopy. Single exponential relaxation kinetics were observed and fit with a two-state model. The folding rate determined for these cyclic peptides is accelerated by some two orders of magnitude over the rate of a linear peptide that forms a beta-hairpin. This observation supports the argument that the rate limiting step in the linear system is either stabilization of compact collapsed structures or rearrangement of collapsed structures over a barrier to achieve the native interstrand registry. Small activation energies for folding of these peptides obtained from an Arrhenius analysis of the rates imply a primarily entropic barrier, hence an organized transition state having specific stabilizing interactions.     

Computational and experimental determination of the alpha-helix unfolding reaction coordinate

We demonstrate a calculated alpha-helix peptide folding energy landscape which accurately simulates the first experimentally measured alpha-helix melting energy landscape. We examine a 21-amino acid, mainly polyalanine peptide and calculate the free energy along the Psi Ramachandran angle secondary folding coordinate. The experimental free energy landscape was determined using UV resonance Raman spectroscopy. The relative free energy values are very close as are the equilibrium peptide conformations. We find 2.3 kcal/mol activation barriers between the alpha-helix-like and PPII-like basins. We also find that the alpha-helix-like conformations are quite defective and the alpha-helix-like structure dynamically samples 310-helix and pi-bulges.     

Minimal model for studying prion-like folding pathways

The Monte Carlo technique is used to simulate the energy landscape and the folding kinetics of a minimal prion-like protein model. We show that the competition between hydrogen-bonding and hydrophobic interactions yields two energetically favored secondary structures, an alpha-helix and a beta-hairpin. Folding simulations indicate that the probability of reaching the alpha-helix form from a denatured random conformation is much higher than the probability of reaching the beta-sheet form, even though the beta-sheet has a lower energy. The existence of a lower energy beta-sheet state gives the possibility for the normal alpha-helix structure to take a structural transformation into the beta-sheet structure under external influences.