Electrostatic effects on the alpha-helix and beta-strand formation of BPTI(16-36) studied by Monte Carlo simulated annealing.

The electrostatic effects on the secondary structure forming tendencies of a peptide fragment with residues 16-36 of bovine pancreatic trypsin inhibitor, BPTI(16-36), are studied using Monte Carlo simulated annealing simulations. We consider three dielectric functions epsilon(r) of distance r: constant dielectric function (epsilon = 2; strong electrostatic interactions) and sigmoidal functions varying from epsilon(0) = 2 to epsilon(infinity) = 47 (intermediate) and to epsilon(infinity) = 78 (weak). Simulations with epsilon = 2 suggest that this peptide exhibits a significant propensity for beta-strand formations in accordance with a beta-sheet structure of the relevant segment in native BPTI. The tendency for alpha-helix formations becomes almost comparable with that of beta-strands in the simulation with epsilon(infinity) = 47, and there appears no appreciable conformational propensity for this case. Finally, the results with epsilon(infinity) = 78 generate low-energy conformations with conspicuous alpha-helices. These findings suggest the possibility that the change in electrostatic interactions can be the key factor for the conformational transitions of peptides between alpha-helix and beta-sheet that have recently been observed in experiments. These changes in electrostatic interactions can arise from those in various environmental factors such as conformations of the rest of the protein molecule and solvent conditions.     

The loop problem in proteins: A monte carlo simulated annealing approach

A Monte Carlo simulated annealing (MCSA) algorithm was used to generate the conformations of local regions in bovine pancreatic trypsin inhibitor (BPTI) starting from random initial conformations. In the approach explored, only the conformation of the segment is computed; the rest of the protein is fixed in the known native conformation. Rather than follow a single simulation exhaustively, computer time is better used by performing multiple independent MCSA simulations in which different starting temperatures are employed and the number of conformations sampled is varied. The best computed conformation is chosen on the basis of lowest total energy and refined further. The total energy used in the annealing is the sum of the intrasegment energy, the interaction energy of the segment with the local surrounding region, and a distance constraint to generate a smooth connection of the initially randomized segment with the rest of the protein. The rms deviations between the main-chain conformations of the computed segments in BPTI and those of the native x-ray structure are 0.94 Å for a 5-residue α-helical segment, 1.11 Å for a 5-residue β-strand segment, and 1.03, 1.61, and 1.87 Ã for 5-, 7-, and 9-residue loop segments. Side-chain deviations are comparable to the main-chain deviations for those side chains that interact strongly with the fixed part of the protein. A detailed view of the deviations at an atom-resolved level is obtained by comparing the predicted segments with their known conformations in the crystal structure of BPTI. These results emphasize the value of predetermined fixed structure against which the computed segment can nest. © 1993 John Wiley & Sons, Inc.     

Molecular dynamics simulation of Escherichia coli dihydrofolate reductase and its protein fragments: relative stabilities in experiment and simulations

We have carried out molecular dynamics simulations of the native dihydrofolate reductase from Escherichia coli and several of its folded protein fragments at standard temperature. The simulations have shown fragments 1--36, 37--88, and 89--159 to be unstable, with a C(alpha)RMSD (C(alpha) root mean squared deviation) >5 A after 3.0 nsec of simulation. The unfolding of fragment 1--36 was immediate, whereas fragments 37--88 and 89--159 gradually unfolded because of the presence of the beta-sheet core structure. In the absence of residues 1--36, the two distinct domains comprising fragment 39--159 associated with each other, resulting in a stable conformation. This conformation retained most of its native structural elements. We have further simulated fragments derived from computational protein cutting. These were also found to be unstable, with the exception of fragment 104--159. In the absence of alpha(4), the loose loop region of residues 120--127 exhibited a beta-strand-like behavior, associating itself with the beta-sheet core of the protein fragment. The current study suggests that the folding of dihydrofolate reductase involves cooperative folding of distinct domains which otherwise would have been unstable as independent folded units in solution. Finally, the critical role of residues 1--36 in allowing the two distinct domains of fragment 104--159 to fold into the final native conformation is discussed.     

An N-terminal fragment of barnase has residual helical structure similar to that in a refolding intermediate.

A fragment of barnase comprising amino acids 1 to 36 (B(1-36)) that encompasses the region containing the two large helices (residues 6-18 and 26-34) of the native protein has been obtained by cleavage of the barnase mutant Val36----Met with cyanogen bromide. The circular dichroism (c.d.) spectrum of B(1-36) in the far ultraviolet indicates that the fragment is only weakly structured in water at neutral pH. The two-dimensional 1H nuclear magnetic resonance spectrum of B(1-36) shows, however, that a fraction of the population does have helical structure, spanning amino acid residues 8 to 18. B(1-36) becomes more helical in 35% trifluoroethanol. This is indicated by the c.d. spectrum and the increase from 6.6 to 7.0 in the pKa of His18, which is known to interact with the dipole of helix 6-18 in native barnase. The helical region of B(1-36) in 35% trifluoroethanol extends to residue 6. It is calculated from extrapolation of a trifluoroethanol titration of the ellipticity at 222 nm that B(1-36) exhibits in water approximately 6% of helical structure, calculated for a 36 residue alpha-helical peptide. This corresponds to approximately 20% of that expected for an 11-residue alpha-helical region. In trifluoroethanol, c.d. measurements indicate that approximately 30% of the 36-residue peptide is helical. It has been shown from extensive studies of the refolding of barnase that there is a folding intermediate that contains residues 8 to 18 in a helical conformation and that residue 6 is mainly unfolded. The experiments on the conformation of B(1-36) show that a small, but significant fraction, of its population in water adopts the conformation of the major alpha-helix during the barnase folding pathway, in the absence of tertiary interactions. Thus, in the folding of native barnase, secondary structure formation can precede the docking of the major alpha-helix onto the beta-sheet.     

Synthesis and characterization of a pancreatic trypsin inhibitor homologue and a model inhibitor.

The synthesis and characterization of protein proteinase inhibitor homologues with variations in the amino acid composition in the vicinity of the reactive site should aid the understanding of the mechanism by which inhibition of enzymatic activity occurs. A homologue inhibitor in which the reactive-site residue Ala-16 of basic pancreatic trypsin inhibitor (Kunitz) (BPTI) is replaced by Phe has been synthesized to study the effect of this replacement on the dissociation constants of the enzyme-inhibitor complexes. The replacement of Ala-16 by Phe causes a dramatic increase in the K1 value of the trypsin-BPTI complex while that of the chymotrypsin-BPTI complex remains essentially the same. This cannot be explained simply in terms of increased steric crowding. The Phe replacement probably causes a small change in the local conformation of the reactive site of the inhibitor which leads to a large decrease in the stability of the very tight trypsin-BPTI complex. This conformation change apparently can be tolerated in the less tightly bound chymotrypsin-BPTI complex. On the basis of the known structure of BPTI, a cyclic heptadecapeptide containing one disulfide bond was synthesized as a model inhibitor in order to determine if a smaller peptide can be designed to act as a highly efficient inhibitor for trypsin. This heptadecapeptide which contains all of the amino acid residues of BPTI taking part in the interaction of the proteinase inhibitor with trypsin binds 3 X 10(7) time more weakly to the enzyme than native BPTI does. It thus appears that even though only a small part of the inhibitor molecule enters directly into interaction with the enzyme, the remaining portions of the molecule which hold the structure of the inhibitor rigid are essential for the strong interaction.     

The energetic cost of induced fit catalysis: Crystal structures of trypsinogen mutants with enhanced activity and inhibitor affinity

The contribution of induced fit to enzyme specificity has been much debated, although with little experimental data. Here we probe the effect of induced fit on enzyme specificity using the trypsin(ogen) system. BPTI is known to induce trypsinogen to assume a trypsinlike conformation. Correlations are observed between BPTI affinity and the values of k(cat)/K(m) for the hydrolysis of two substrates by eight trypsin(ogen) variants. The slope of both correlations is -1.8. The crystal structures of the BPTI complexes of four variant trypsinogens were also solved. Three of these enzymes, K15A, DeltaI16V17/D194N, and DeltaI16V17/Q156K trypsinogen, are 10- to 100-fold more active than trypsinogen. The fourth variant, DeltaI16V17 trypsinogen, is the lone outlier in the correlations; its activity is lower than expected based on its affinity for BPTI. The S1 site and oxyanion hole, formed by segments 184A-194 and 216-223, are trypsinlike in all of the enzymes. These structural and kinetic data confirm that BPTI induces an active conformation in the trypsin(ogen) variants. Thus, changes in BPTI affinity monitor changes in the energetic cost of inducing a trypsinlike conformation. Although the S1 site and oxyanion hole are similar in all four variants, the N-terminal and autolysis loop (residues 142-152) segments have different interactions for each variant. These results indicate that zymogen activity is controlled by a simple conformational equilibrium between active and inactive conformations, and that the autolysis loop and N-terminal segments control this equilibrium. Together, these data illustrate that induced fit does not generally contribute to enzyme specificity.     

Synthesis and characterization of a beta-hairpin peptide that represents a 'core module' of bovine pancreatic trypsin inhibitor (BPTI)

A new strategy for the design and construction of peptide fragments that can achieve defined, nativelike secondary structure is presented. The strategy is based upon the hypothesis that 'core elements' of a protein, synthesized in a single polypeptide molecule, will favor nativelike structure, and that by incorporating a cross-link, nativelike core structure will dominate the ensemble as the more extended conformations are excluded. 'Core elements' are the elements of packed secondary structure that contain the slowest exchanging backbone amide protons in the native protein. The 'core elements' in bovine pancreatic trypsin inhibitor (BPTI) are the two long strands of antiparallel beta-sheet (residues 18-24 and 29-35) and the small beta-bridge (residues 43-44). To test the design strategy, we synthesized an 'oxidized core module', which contains the antiparallel strands connected by a modified reverse turn (A27 replaced by D), a natural disulfide cross-link at the open end of the hairpin, and N- and C-termini blocking groups. A peptide with identical sequence but lacking the disulfide cross-link at the open end was used as the 'reduced core module' control. The conformational behavior of both peptides was examined using (1)H NMR spectroscopy. Chemical shift dispersion, chemical shift deviation from random coil values, sequential and long-range NOEs, and H/D amide exchange rates were compared for the two peptides. We conclude that the ensemble of oxidized and reduced core module conformations samples both nativelike 4:4 and non-native 3:5 beta-hairpin structure, and that the oxidized module samples nativelike structure for a greater fraction of the time than the reduced module.     

Pi7, an orphan peptide from the scorpion Pandinus imperator: a 1H-NMR analysis using a nano-NMR Probe

The three-dimensional solution structure of a novel peptide, Pi7, purified from the venom of the scorpion Pandinus imperator, and for which no specific receptor has been found yet, was determined by two-dimensional homonuclear proton NMR methods from a nanomole amount of compound using a nano-nmr probe. Pandinus imperator peptide 7 does not block voltage-dependent K(+)-channels and does not displace labeled noxiustoxin from rat brain synaptosomal membranes. The toxin has 38 amino acid residues and, similarly to Pi1, is stabilized by four disulfide bridges (Cys6-Cys27, Cys12-Cys32, Cys16-Cys34, and Cys22-Cys37). In addition, the lysine at position 26 crucial for potassium-channel blocking is replaced in Pi7 by an arginine. Tyrosine 34, equivalent to Tyr36 of ChTX is present, but the N-terminal positions 1 and 2 are occupied by two acidic residues Asp and Glu, respectively. The dihedral angles and distance restraints obtained from measured NMR parameters were used in structural calculations in order to determine the conformation of the peptide. The disulfide-bridge topology was established using distance restraints allowing ambiguous partners between S atoms combined with NMR-derived structural information. The structure is organized around a short alpha-helix spanning residues Thr9 to Thr20/Gly21 and a beta-sheet. These two elements of secondary structure are stabilized by two disulfide bridges, Cys12-Cys32 and Cys16-Cys34. The antiparallel beta-sheet is composed of two strands extending from Asn22 to Cys34 with a tight turn at Ile28-Asn29 in contact with the N-terminal fragment Ile4 to Cys6.     

Secondary structure of bovine beta-lactoglobulin B

Secondary-structure-prediction algorithms have been used to find the segments of beta-lactoglobulin sequence most likely to fit the circular dichroism assignment of 15% alpha-helix, 50% beta-sheet, and 15-20% reverse turn. A number of segments may have an alpha-helical conformation but the most prominent region of alpha-helix is from residue 129 to 143. A further probable alpha-helix segment is residues 65-76. The number of residues predicted to occur in segments of beta-sheet structure is less than expected. However, the most likely segments are for residues 1-6, 11-16, 39-45, 80-85, 92-96, 101-107, 117-123, and 145-151. Predicted reverse-turn tetrapeptides are residues 7-10, 49-52, 61-64, 88-91, and 112-115. These predicted secondary structures are consistent with the low-resolution structure of the molecule determined by X-ray diffraction studies.     

Surface active properties of amphiphilic sequential isopeptides: Comparison between alpha-helical and beta-sheet conformations

Poly(Leu-Lys-Lys-Leu) and poly(Leu-Lys) are sequential amphiphilic peptide isomers that adopt respectively an alpha-helical conformation and a beta-sheet structure in saline solutions and at the air/water interface. The surface active properties of LKKL and LK sequential isopeptides containing 16, 20, and n residues have been compared in order to evaluate the contributions of the alpha-helical and beta-sheet conformations. Both have a natural tendency to spread at the surface of a saline solution and the values of the equilibrium spreading pressure pi(e) lie in the same range. When dissolved in a saline solution, alpha-helical peptides diffuse faster and adsorb faster at the interface than the beta-sheet isomers. From the compression isotherms of LKKL and LK peptide monolayers it is possible to extract parameters that characterize the behavior of alpha-helical and beta-sheet conformations: beta-sheet peptide monolayers are more stable and less compressible than the monolayers formed with the alpha-helical isomers. The LK peptides differ also by their high degree of self-association at the air/water interface. Copyright 1999 John Wiley & Sons, Inc.     

Molecular thermodynamic model to predict the alpha-helical secondary structure of polypeptide chains in solution.

The native state of a protein molecule in aqueous solutions represents one of the lowest states of Gibbs energy [Anfinsen, C.B. (1973) Science 181, 223-230]. Much progress has been made about the rules of protein folding [King, J. (1989) Chem. Eng. News 67, 32-54] and the dominant forces in protein folding [Dill, K.A. (1990) Biochemistry 29, 7133-7155]. However, the quantitative contributions of different Gibbs energy terms to protein stability remains a controversial issue [Moult, J., & Unger, R. (1991) Biochemistry 30, 3816-3824]. A molecular thermodynamic model has been proposed for the Gibbs energy of folding a residue in aqueous homopolypeptides from a random-coiled state to either the alpha-helix state or the beta-sheet state [Chen, C.-C., Zhu, Y., King, J.A., & Evans, L.B. (1992) Biopolymers 32, 1375-1392]. In this work, we present a generalization of the molecular thermodynamic model for the Gibbs energy of folding natural and synthetic heteropolypeptides from random-coiled conformations into alpha-helical conformations. The generalized model incorporates the intrinsic folding potential due to residue-solvent interactions, the cooperative folding effect due to residue-residue interactions, and the location and length of alpha-helices. The utility of the model was demonstrated by examining the stability of alpha-helical conformations of a number of natural polypeptides including C-peptide (residues 1-13) and S-peptide (residues 1-20) of RNase A (bovine pancreatic ribonuclease A), the P alpha fragment in BPTI (bovine pancreatic trypsin inhibitor), and synthetic polypeptides (the copolymers of different amino acid residues) including alanine-based peptides (16 or 17 residues long) in water. The computed Gibbs energies correspond well with the experimental data on helicity. The results also accounted for the effects of amino acid substitution and temperature on the stability of alpha-helical conformations of the test polypeptides.     

Antimicrobial peptide, tachyplesin I, isolated from hemocytes of the horseshoe crab (Tachypleus tridentatus). NMR determination of the beta-sheet structure

The conformation of tachyplesin I, an antimicrobial cationic peptide of 17 residues found in the hemocyte debris of horseshoe crab, was investigated using two-dimensional NMR spectroscopy. The 1H NMR spectrum of tachyplesin I in aqueous solution could be completely assigned, and the secondary structure was substantiated by interpretation of the nuclear Overhauser effect, coupling constant, amide exchange rate, and temperature dependence of the amide chemical shift. Tachyplesin I takes on a fairly rigid conformation constrained by two disulfide bridges and adopts a conformation consisting of an anti-parallel beta-sheet (residues 3-8 and 11-16) connected by a beta-turn (residues 8-11). In this planar conformation, five bulky hydrophobic side groups are localized in one side of the plane and six cationic side groups are distributed at the "tail" part of the molecule (residues 1-5 and 14-17). This amphipathic structure of the molecule is presumed to be closely associated with the bactericidal activity.     

Alpha-helix folding by Monte Carlo simulated annealing in isolated C-peptide of ribonuclease A

Conformation of the C-peptide fragment of RNase A is calculated by Monte Carlo simulated annealing. We adopt the total potential energy as given by the sum of generic interatomic energies whose parameters are determined separately for each amino acid without referring to the empirical structure of the C-peptide. The simulation is carried out in a completely unrestricted way without imposing any weight towards given final destinations. Starting from completely random initial conformations and minimizing the total potential energy with respect to main-chain dihedral angles and side-chain torsion angles, we have obtained partial alpha-helix structure with a high probability (approximately 40%). The energetically most favourable structure exhibits a 2.5-turn alpha-helix at the location identical with that of the 3-turn alpha-helix in the native enzyme molecule. Classification of conformations obtained in the simulation into clusters of similar structure shows that our simulation indeed predicts the alpha-helix structure for the isolated C-peptide with specific charged residues. The results of simulation with various amino acid substitutions are also found to be consistent with the experimental implication for the importance of intramolecular ionic interactions for alpha-helix stability for this peptide.     

Hydrogen bonding monitored by deuterium isotope effects on carbonyl 13C chemical shift in BPTI: intra-residue hydrogen bonds in antiparallel beta-sheet.

Deuterium isotope effects on carbonyl 13C magnetic shielding were measured for the backbone carbonyl groups in BPTI (basic pancreatic trypsin inhibitor), and interpreted as a measure of hydrogen bond energies. The effects originate from peptide amide proton deuterium substitution and were observed on carbonyl carbons separated by two or three covalent bonds from the amide H/D. Two-bond isotope effects depend on the energy of the hydrogen bond donated by NH/D. Calibration of the effect with model compound data leads to hydrogen bond enthalpies less than 4.7 kcal/mol. Isotope effects over three bonds from the amide H/D to the carbonyl carbon of the same amino acid residue are observed for seven carbonyl resonances in BPTI. The three-bond isotope effects are highly related to the various backbone conformations. The largest effects are observed for residues with an approximate syn- periplanar conformation of the H-N-C alpha-C = O atoms, as realized for many residues in the BPTI antiparallel beta-sheet. The residues that show measurable three-bond effects have unusually short distances between H and O. The size of this effect decreases rapidly with increased O..H distance in the open five-membered ring. This observation suggests appreciable interactions in these rings.     

Stability of protein-bound conformations of bioactive peptides: the folded conformation of an epidermal growth factor-like thrombomodulin fragment is similar to that recognized by thrombin

The relationship between the free and bound conformations of bioactive peptides is explored using the epidermal growth factor (EGF)-like thrombomodulin fragment hTM409-426 as a model system. The hTM409-426 peptide has a sequence of C(409)PEGYILDDGFIC(421)TDIDE (with a disulfide bond between Cys409 and Cys421) and is a selective inhibitor of thrombin. Upon binding to thrombin, hTM409-426 adopts a well-defined conformation-namely, a beta-turn followed by an antiparallel beta-sheet, similar to those found in all other EGF-like protein repeats (Hrabal et al., Protein Science, 1996, Vol. 5, 195-203). Here we demonstrate that, at pH 6.8 and at 25 degrees C, the hTM409-426 peptide in the free state is very flexible, but still populates a type II beta-turn over residues Pro410-Glu411-Gly412-Tyr413 and the clustering of some hydrophobic side chains, both of which are present in the thrombin-bound conformation. At a lower temperature of 5 degrees C, significant conformational shifts of the C alpha H proton resonances and extensive medium- and long-range NOEs are observed, indicating the presence of folded conformations with unique backbone-backbone and side-chain interactions. A comparison of the NOE patterns in the free state with transferred NOEs shows that the free-state folded and the thrombin-bound conformations of the hTM409-426 peptide are very similar, particularly over residues Pro410-Ile424. The folded conformation of hTM409-426 appears to be stabilized by two hydrophobic clusters, one formed by the side chains of residues Pro410, Tyr413, Leu415, and Phe419 and the Cys409-Cys421 disulfide bond, the second involving residues Ile414 and Ile424. These results indicate that the overall topology of the thrombin-bound conformation of the hTM409-426 peptide is prefolded in the free state and the primary sequence (including the disulfide bond) may be selective for an ensemble of conformations similar to that recognized by thrombin.     

Insight into the factors influencing the backbone dynamics of three homologous proteins,dendrotoxins I and K,and BPTI: FTIR and time-resolved fluorescence investigations

Attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy, combined with hydrogen/deuterium exchange technique and time-resolved fluorescence spectroscopy, has been used to investigate the changes in structure and dynamics that underlie the thermodynamic stability differences observed for three closely homologous proteins: dendrotoxins I and K, and bovine pancreatic trypsin inhibitor (BPTI). The experiments were performed on proteins under their native state and a modified form, obtained by selective reduction of a disulfide bond at the surface of the molecule, increasing slightly the backbone flexibility without changing the average structure. The data confirmed the high local as well as global rigidity of BPTI. In protein K, the exchange process was slow during the first 2 h of exchange, presumably reflecting a compact three-dimensional conformation, and then increased rapidly, the internal amide protons of the beta-strands exchanging 10-fold faster than in BPTI or protein I. The most probable destabilizing element was identified as Pro32, in the core of the beta-sheet. Protein I was found to present a 10% more expanded volume than protein K or BPTI, and there is a possible correlation between the resulting increased flexibility of the molecule and the lower thermodynamic stability observed for this protein. Interestingly, the interior amide protons of the beta-sheet structure were found to be as protected against exchange in protein I as in BPTI, suggesting that, although globally more flexible than that of Toxin K or BPTI, the structure of Toxin I could be locally quite rigid. The structural factors suspected to be responsible for the differences in internal flexibility of the two toxins could play a significant role in determining their functional properties.     

Folding of the twisted beta-sheet in bovine pancreatic trypsin inhibitor

The dominant role of local interactions has been demonstrated for the formation of the strongly twisted antiparallel beta-sheet structure consisting of residues 18-35 in bovine pancreatic trypsin inhibitor. Conformational energy minimization has indicated that this beta-sheet has a strong twist even in the absence of the rest of the protein molecule. The twist is maintained essentially unchanged when energy minimization is carried out by starting from the native conformation. By starting from a nontwisted beta-sheet conformation of residues 18-35, a strongly twisted structure (higher in energy than the native) is obtained. The high twist of the native-like beta-sheet is a consequence of its amino acid sequence, but it is enhanced strongly by interchain interactions that operate within the beta-sheet. The existence of the twisted beta-sheet structure does not require the presence of a disulfide bond between residue 14 and residue 38. It actually may facilitate the formation of this bond. Therefore, it is likely that the beta-sheet structure forms during an earlier stage of folding than the formation of this disulfide bond. This study provides an example of the manner in which conformational energy calculations can be used to provide information about the probable pathway of the folding of a protein.     

Synthesis, folding, and structure of the beta-turn mimic modified B1 domain of streptococcal protein G

The mechanism of beta-sheet formation remains a fundamental issue in our understanding of the protein folding process, but is hampered by the often encountered kinetic competition between folding and aggregation. The role of local versus nonlocal interactions has been probed traditionally by mutagenesis of both turn and strand residues. Recently, rigid organic molecules that impose a correct chain reversal have been introduced in several small peptides to isolate the importance of the long-range interactions. Here, we present the incorporation of a well-studied beta-turn mimic, designated as the dibenzofuran-based (DBF) amino acid, in the B1 domain of streptococcal protein G (B1G), and compare our results with those obtained upon insertion of the same mimic into the N-terminal beta-hairpin of B1G (O Melnyk et al., 1998, Lett Pept Sci 5:147-150). The DBF-B1G domain conserves the structure and the functional and thermodynamical properties of the native protein, whereas the modified peptide does not adopt a native-like conformation. The nature of the DBF flanking residues in the modified B1G domain prevents the beta-turn mimic from acting as a strong beta-sheet nucleator, which reinforces the idea that the native beta-hairpin formation is not driven by the beta-turn formation, but by tertiary interactions.     

Model of Alzheimer's disease amyloid-beta peptide based on a RNA binding protein

Although Alzheimer's Abeta peptide has been shown to form beta-sheet structure, a high-resolution molecular structure is still unavailable to date. A search for a sequence neighbor using Abeta(10-42) as the query in the Protein Data-Bank (PDB) revealed that an RNA binding protein, AF-Sm1 from Archaeoglobus fulgidus (PDB entry: 1i4k chain Z), shared 36% identical residues. Using AF-Sm1 as a template, we built a molecular model of Abeta(10-42) by applying comparative modeling methods. The model of Abeta(10-42) contains an antiparallel beta-sheet formed by residues 16-23 and 32-41. Hydrophobic surface constituted by residues 17-20 (LVFF) separates distinctly charged regions. Residues that interact with RNA in the AF-Sm1 crystal structure were found to be conserved in Abeta. Using a native gel we demonstrate for the first time that RNA can interact with Abeta and selectively retard the formation of fibrils or higher-order oligomers. We hypothesize that in a similar fashion to AF-Sm1, RNA interacts with Abeta in the beta-hairpin (beta-turn-beta) structure and prevents fibril formation.