Current Protein & Peptide Science[JOURNAL]
Sun
168 papers
Design, synthesis, and evaluation of peptides with estrogen-like activity.
Kasher R, Gayer B, Kulik T … +5 more , Somjen D, Venkatesh N, Fridkin M, Katchalski-Katzir E, Kohen F
Biopolymers · 2004 · PMID 15468062 · Publisher ↗
Currently used antiestrogenic drugs against hormone-dependent breast cancer, and estrogenic drugs used in treatment of osteoporosis, are associated with risk factors. Therefore, there is a strong need to develop selectiv...
Currently used antiestrogenic drugs against hormone-dependent breast cancer, and estrogenic drugs used in treatment of osteoporosis, are associated with risk factors. Therefore, there is a strong need to develop selective estrogen receptor modulators with better tissue selectivity. In a recent study (Peptides, 2002, Vol. 3, 573-580), we used a monoclonal antibody to estradiol (mAb-E2) to screen a phage-display peptide library. We identified a 15-mer peptide (peptide H5) that recognizes mAb-E2 (IC(50) 1 microM) and estrogen receptor (ER)alpha (IC(50) 500 microM) but not ERbeta, and displays estrogen-like activity in vitro and in vivo. In this study, we designed and prepared peptides based on peptide H5, which possess improved estrogenic activity, by evaluating their binding to mAb-E2 and to ERs. Initially, we determined the minimal binding sequence of peptide H5 capable of binding mAb-E2 and ER. Subsequently, systematic single-residue replacements of the minimal sequence, followed by multiple-residue replacements, yielded hexa- and heptapeptides with increased affinities to mAb-E2 and to ER. The most promising peptides, VSWFFE (EMP-1) and VSWFFED (EMP-2) (EMP: estrogen-mimetic peptide), bind mAb-E2 with high affinity (IC(50) of 6 and 30 nM, respectively), recognize ERs with increased affinity (IC(50) of 100 microM for ERalpha, and 100-250 microM for ERbeta), and possess estrogenic activity in vivo. The short peptides described in this study may be used as potential lead compounds for developing new ER ligands.
Beta2-amino acids-syntheses, occurrence in natural products, and components of beta-peptides1,2.
Lelais G, Seebach D
Biopolymers · 2004 · PMID 15148683 · Publisher ↗
Although they are less abundant than their alpha-analogues, beta-amino acids occur in nature both in free form and bound to peptides. Oligomers composed exclusively of beta-amino acids (so-called beta-peptides) might be...
Although they are less abundant than their alpha-analogues, beta-amino acids occur in nature both in free form and bound to peptides. Oligomers composed exclusively of beta-amino acids (so-called beta-peptides) might be the most thoroughly investigated peptidomimetics. Beside the facts that they are stable to metabolism, exhibit slow microbial degradation, and are inherently stable to proteases and peptidases, they fold into well-ordered secondary structures consisting of helices, turns, and sheets. In this respect, the most intriguing effects have been observed when beta2-amino acids are present in the beta-peptide backbone. This review gives an overview of the occurrence and importance of beta2-amino acids in nature, placing emphasis on the metabolic pathways of beta-aminoisobutyric acid (beta-Aib) and the appearance of beta2-amino acids as secondary metabolites or as components of more complex natural products, such as peptides, depsipeptides, lactones, and alkaloids. In addition, a compilation of the syntheses of both achiral and chiral beta2-amino acids is presented. While there are numerous routes to achiral beta2-amino acids, their EPC synthesis is currently the subject of many investigations. These include the diastereoselective alkylation and Mannich-type reactions of cyclic- or acyclic beta-homoglycine derivatives containing chiral auxiliaries, the Curtius degradation, the employment of transition-metal catalyzed reactions such as enantioselective hydrogenations, reductions, C-H insertions, and Michael-type additions, and the resolution of rac. beta2-amino acids, as well as several miscellaneous methods. In the last part of the review, the importance of beta2-amino acids in the formation of beta-peptide secondary structures is discussed.
Molecular spacers for physicochemical investigations based on novel helical and extended peptide structures.
Toniolo C, Crisma M, Formaggio F … +3 more , Peggion C, Broxterman QB, Kaptein B
Biopolymers · 2004 · PMID 15054896 · Publisher ↗
A proper understanding of the detailed nature and mechanism of physicochemical interactions depends heavily upon our ability to design and synthesize conformationally constrained 3D structures whose intercomponent geomet...
A proper understanding of the detailed nature and mechanism of physicochemical interactions depends heavily upon our ability to design and synthesize conformationally constrained 3D structures whose intercomponent geometry (either rigorously rigid or able to undergo destructuration, if required, but in all cases precisely tunable) would be well defined. To this end we have recently reported a few initial studies and we are currently working on the exploitation of stable, short, helical peptide spacers based on achiral and/or chiral Calpha-tetrasubstituted alpha-amino acids. These building blocks are known to force the peptides either to predominantly fold into a 3(10)-helical structure or to adopt a fully extended, planar 2.0(5)-helix. The systems under investigation involve a donor and an acceptor moiety linked to the N- and C-termini of the oligopeptide spacer main chain. By increasing the number of intervening residues the donor.acceptor separation can be easily modulated. This review highlights details of these two novel peptide secondary structures and their use as molecular spacers in physicochemical investigations.
Side-chain anchoring strategy for solid-phase synthesis of peptide acids with C-terminal cysteine.
Barany G, Han Y, Hargittai B … +2 more , Liu RQ, Varkey JT
Biopolymers · 2003 · PMID 14991675 · Publisher ↗
Many naturally occurring peptide acids, e.g., somatostatins, conotoxins, and defensins, contain a cysteine residue at the C-terminus. Furthermore, installation of C-terminal cysteine onto epitopic peptide sequences as a...
Many naturally occurring peptide acids, e.g., somatostatins, conotoxins, and defensins, contain a cysteine residue at the C-terminus. Furthermore, installation of C-terminal cysteine onto epitopic peptide sequences as a preliminary to conjugating such structures to carrier proteins is a valuable tactic for antibody preparation. Anchoring of N(alpha)-Fmoc, S-protected C-terminal cysteine as an ester onto the support for solid-phase peptide synthesis is known to sometimes occur in low yields, has attendant risks of racemization, and may also result in conversion to a C-terminal 3-(1-piperidinyl)alanine residue as the peptide chain grows by Fmoc chemistry. These problems are documented for several current strategies, but can be circumvented by the title anchoring strategy, which features the following: (a). conversion of the eventual C-terminal cysteine residue, with Fmoc for N(alpha)-amino protection and tert-butyl for C(alpha)-carboxyl protection, to a corresponding S-xanthenyl ((2)XAL(4)) preformed handle derivative; and (b). attachment of the resultant preformed handle to amino-containing supports. This approach uses key intermediates that are similar to previously reported Fmoc-XAL handles, and builds on earlier experience with Xan and related protection for cysteine. Implementation of this strategy is documented here with syntheses of three small model peptides, as well as the tetradecapeptide somatostatin. Anchoring occurs without racemization, and the absence of 3-(1-piperidinyl)alanine formation is inferred by retention of chains on the support throughout the cycles of Fmoc chemistry. Fully deprotected peptides, including free sulfhydryl peptides, are released from the support in excellent yield by using cocktails containing a high concentration (i.e., 80-90%) of TFA plus appropriate thiols or silanes as scavengers. High-yield release of partially protected peptides is achieved by treatment with cocktails containing a low concentration (i.e., 1-5%) of TFA. In peptides with two cysteine residues, the corresponding intramolecular disulfide-bridged peptide is obtained by either (a). oxidation, in solution, of the dithiol product released by acid; (b). simultaneous acidolytic cleavage and disulfide formation, achieved by addition of the mild oxidant DMSO to the cleavage cocktail; or (c). concomitant cleavage/cooxidation (involving a downstream S-Xan protected cysteine), using reagents such as iodine or thallium tris(trifluoroacetate) in acetic acid.
Local sequence information in cellular retinoic acid-binding protein I: specific residue roles in beta-turns.
Rotondi KS, Gierasch LM
Biopolymers · 2003 · PMID 14991674 · Publisher ↗
We have recently shown that two of the beta-turns (III and IV) in the ten-stranded, beta-clam protein, cellular retinoic acid-binding protein I (CRABP I), are favored in short peptide fragments, arguing that they are enc...
We have recently shown that two of the beta-turns (III and IV) in the ten-stranded, beta-clam protein, cellular retinoic acid-binding protein I (CRABP I), are favored in short peptide fragments, arguing that they are encoded by local interactions (K. S. Rotondi and L. M. Gierasch, Biochemistry, 2003, Vol. 42, pp. 7976-7985). In this paper we examine these turns in greater detail to dissect the specific local interactions responsible for their observed native conformational biases. Conformations of peptides corresponding to the turn III and IV fragments were examined under conditions designed to selectively disrupt stabilizing interactions, using pH variation, chaotrope addition, or mutagenesis to probe specific side-chain influences. We find that steric constraints imposed by excluded volume effects between near neighbor residues (i,i+2), favorable polar (i,i+2) interactions, and steric permissiveness of glycines are the principal factors accounting for the observed native bias in these turns. Longer-range stabilizing interactions across the beta-turns do not appear to play a significant role in turn stability in these short peptides, in contrast to their importance in hairpins. Additionally, our data add to a growing number of examples of the 3:5 type I turn with a beta-bulge as a class of turns with high propensity to form locally defined structure. Current work is directed at the interplay between the local sequence information in the turns and more long-range influences in the mechanism of folding of this predominantly beta-sheet protein.
Spectroscopic evidence revealing polyproline II structure in hydrophobic, putatively elastomeric sequences encoded by specific exons of human tropoelastin.
Bochicchio B, Aït-Ali A, Tamburro AM … +1 more , Alix AJ
Biopolymers · 2004 Mar · PMID 14991666 · Publisher ↗
Elastin, the protein responsible for tissue elasticity, is contained in arterial walls, lungs, and skin. Given the cassette like organization of the human tropoelastin gene, giving rise to alternating exons encoding for...
Elastin, the protein responsible for tissue elasticity, is contained in arterial walls, lungs, and skin. Given the cassette like organization of the human tropoelastin gene, giving rise to alternating exons encoding for crosslink domains and elastomeric domains, it is tempting to suggest that polypeptides encoded by different exons could adopt structures independent of the other exons. The results obtained with the polypeptide sequences encoded by exons 3, 7, and 30 of human tropoelastin are described. It is shown that these hydrophobic exons may partly assume the polyproline II (PPII) structure, as found by circular dichroism studies in aqueous solution. Classical Raman spectroscopy evidences a specific sharp band at 1314 cm(-1), which is assigned to the PPII structure adopted by these exons in the solid state. As these sequences are among those putatively responsible for elastomeric properties, these findings are of particular interest in relation to the current models of the elasticity of elastin.
New approaches to targeting RNA with oligonucleotides: inhibition of group I intron self-splicing.
Disney MD, Childs JL, Turner DH
Biopolymers · 2004 Jan · PMID 14691946 · Publisher ↗
RNA is one class of relatively unexplored drug targets. Since RNAs play a myriad of essential roles, it is likely that new drugs can be developed that target RNA. There are several factors that make targeting RNA particu...
RNA is one class of relatively unexplored drug targets. Since RNAs play a myriad of essential roles, it is likely that new drugs can be developed that target RNA. There are several factors that make targeting RNA particularly attractive. First, the amount of information about the roles of RNA in essential biological processes is currently being expanded. Second, sequence information about targetable RNA is pouring out of genome sequencing efforts at unprecedented levels. Third, designing and screening potential oligonucleotide therapeutics to target RNA is relatively simple. The use of oligonucleotides in cell culture, however, presents several challenges such as oligonucleotide uptake and stability, and selective targeting of genes of interest. Here, we review investigations aimed at targeting RNA with oligonucleotides that can circumvent several of these potential problems. The hallmark of the strategies discussed is the use of short oligonucleotides, which may have the advantage of higher cellular uptake and improved binding selectivity compared to longer oligonucleotides. These strategies have been applied to Group I introns from the mammalian pathogens Pneumocystis carinii and Candida albicans. Both are examples of fungal infections that are increasing in number and prevalence.
Catalytic roles for proton transfer and protonation in ribozymes.
Bevilacqua PC, Brown TS, Nakano S … +1 more , Yajima R
Biopolymers · 2004 Jan · PMID 14691943 · Publisher ↗
Utilization of proton transfer in catalysis, which is well known in the mechanisms of protein enzymes, has been described only relatively recently for RNA enzymes. In this article, we present a current understanding of p...
Utilization of proton transfer in catalysis, which is well known in the mechanisms of protein enzymes, has been described only relatively recently for RNA enzymes. In this article, we present a current understanding of proton transfer by nucleic acids. Rate enhancement and specificity conferred by general acid-base catalysis are discussed. We also present possibilities for electrostatic catalysis from general acids and bases as well as cationic base pairs. The microenvironments of a large RNA provide the possibility of histidine-like pK(a)s for proton transfer, as well as lysine- and arginine-like pK(a)s for electrostatic catalysis. Discussion on proton transfer focuses on the hepatitis delta virus (HDV) and hairpin ribozymes, with select examples drawn from the protein literature. Discussion on electrostatic catalysis also draws on these two ribozymes, and a postulate for electrostatic catalysis by a cationic base pair in the mechanism of peptidyl transfer in the ribosome is presented. We also provide a perspective on possibilities for phosphoryl transfer mechanisms involving phosphorane intermediates and unusual tautomeric forms of the bases. Lastly, a distinction is made between ground state and "transition state" pK(a)s. We favor a model in which changes in pH lead to changes in the distribution of reactive and nonreactive ionizations of the ribozyme molecules in the ground state, and therefore suggest that "pK(a) changes in the transition state" do not provide an acceptable explanation for observed pH-rate profiles.
Application of statistical potentials to protein structure refinement from low resolution ab initio models.
Lu H, Skolnick J
Biopolymers · 2003 Dec · PMID 14648767 · Publisher ↗
Recently ab initio protein structure prediction methods have advanced sufficiently so that they often assemble the correct low resolution structure of the protein. To enhance the speed of conformational search, many ab i...
Recently ab initio protein structure prediction methods have advanced sufficiently so that they often assemble the correct low resolution structure of the protein. To enhance the speed of conformational search, many ab initio prediction programs adopt a reduced protein representation. However, for drug design purposes, better quality structures are probably needed. To achieve this refinement, it is natural to use a more detailed heavy atom representation. Here, as opposed to costly implicit or explicit solvent molecular dynamics simulations, knowledge-based heavy atom pair potentials were employed. By way of illustration, we tried to improve the quality of the predicted structures obtained from the ab initio prediction program TOUCHSTONE by three methods: local constraint refinement, reduced predicted tertiary contact refinement, and statistical pair potential guided molecular dynamics. Sixty-seven predicted structures from 30 small proteins (less than 150 residues in length) representing different structural classes (alpha, beta, alpha;/beta) were examined. In 33 cases, the root mean square deviation (RMSD) from native structures improved by more than 0.3 A; in 19 cases, the improvement was more than 0.5 A, and sometimes as large as 1 A. In only seven (four) cases did the refinement procedure increase the RMSD by more than 0.3 (0.5) A. For the remaining structures, the refinement procedures changed the structures by less than 0.3 A. While modest, the performance of the current refinement methods is better than the published refinement results obtained using standard molecular dynamics.
Recombinant human elastin polypeptides self-assemble into biomaterials with elastin-like properties.
Bellingham CM, Lillie MA, Gosline JM … +5 more , Wright GM, Starcher BC, Bailey AJ, Woodhouse KA, Keeley FW
Biopolymers · 2003 Dec · PMID 14648756 · Publisher ↗
Processes involving self-assembly of monomeric units into organized polymeric arrays are currently the subject of much attention, particularly in the areas of nanotechnology and biomaterials. One biological example of a...
Processes involving self-assembly of monomeric units into organized polymeric arrays are currently the subject of much attention, particularly in the areas of nanotechnology and biomaterials. One biological example of a protein polymer with potential for self-organization is elastin. Elastin is the extracellular matrix protein that imparts the properties of extensibility and elastic recoil to large arteries, lung parenchyma, and other tissues. Tropoelastin, the approximately 70 kDa soluble monomeric form of elastin, is highly nonpolar in character, consisting essentially of 34 alternating hydrophobic and crosslinking domains. Crosslinking domains contain the lysine residues destined to form the covalent intermolecular crosslinks that stabilize the polymer. We and others have suggested that the hydrophobic domains are sites of interactions that contribute to juxtaposition of lysine residues in preparation for crosslink formation. Here, using recombinant polypeptides based on sequences in human elastin, we demonstrate that as few as three hydrophobic domains flanking two crosslinking domains are sufficient to support a self-assembly process that aligns lysines for zero-length crosslinking, resulting in formation of the crosslinks of native elastin. This process allows fabrication of a polymeric matrix with solubility and mechanical properties similar to those of native elastin.
An assessment of protein-ligand binding site polarizability.
Nayeem A, Krystek S, Stouch T
Biopolymers · 2003 Oct · PMID 14517908 · Publisher ↗
Electronic polarizability, an important physical property of biomolecules, is currently ignored in most biomolecular calculations. Yet, it is widely believed that polarization could account for a substantial fraction of...
Electronic polarizability, an important physical property of biomolecules, is currently ignored in most biomolecular calculations. Yet, it is widely believed that polarization could account for a substantial fraction of the total nonbonded energy of a system. This belief is supported by studies of small complexes in vacuum. This perception is driving the development of a new class of polarizable force fields for biomolecular calculations. However, the quantification of this term for protein-ligand complexes has never been attempted. Here we explore the polarizable nature of protein-ligand complexes in order to evaluate the importance of this effect. We introduce two indexes describing the polarizability of protein binding sites. These we apply to a large range of pharmaceutically relevant complexes. We offer a recommendation of particular complexes as test systems with which to determine the effects of polarizability and as test cases with which to test the new generation of force fields. Additionally, we provide a tabulation of the amino acid composition of these binding sites and show that composition can be specific for certain classes of proteins. We also show that the relative abundance of some amino acids is different in binding sites than elsewhere in a protein's structure.
Fluorescence-based methods for evaluating the RNA affinity and specificity of HIV-1 Rev-RRE inhibitors.
Luedtke NW, Tor Y
Biopolymers · 2003 Sep · PMID 12925996 · Publisher ↗
RNA plays a pivotal role in the replication of all organisms, including viral and bacterial pathogens. The development of small molecules that selectively interfere with undesired RNA activity is a promising new directio...
RNA plays a pivotal role in the replication of all organisms, including viral and bacterial pathogens. The development of small molecules that selectively interfere with undesired RNA activity is a promising new direction for drug design. Currently, there are no anti-HIV treatments that target nucleic acids. This article presents the HIV-1 Rev response element (RRE) as an important focus for the development of antiviral agents that target RNA. The Rev binding site on the RRE is highly conserved, even between different groups of HIV-1 isolates. Compounds that inhibit HIV replication by binding to the RRE and displacing Rev are therefore expected to retain activity across groups of genetically diverse HIV infections. Systematic evaluations of both the RRE affinity and specificity of numerous small molecule inhibitors are essential for deciphering the parameters that govern effective RRE recognition. This article discusses fluorescence-based techniques that are useful for probing a small molecule's RRE affinity and its ability to inhibit Rev-RRE binding. Rev displacement experiments can be conducted by observing the fluorescence anisotropy of a fluorescein-labeled Rev peptide, or by quantifying its displacement from a solid-phase immobilized RRE. Experiments conducted in the presence of competing nucleic acids are useful for evaluating the RRE specificity of Rev-RRE inhibitors. The discovery and characterization of new RRE ligands are described. Eilatin is a polycyclic aromatic heterocycle that has at least one binding site on the RRE (apparent Kd is approximately 0.13 microM), but it does not displace Rev upon binding the RRE (IC50 > 3 microM). In contrast, ethidium bromide and two eilatin-containing metal complexes show better consistency between their RRE affinity and their ability to displace a fluorescent Rev peptide from the RRE. These results highlight the importance of conducting orthogonal binding assays that establish both the RNA affinity of a small molecule and its ability to inhibit the function of the RNA target. Some Rev-RRE inhibitors, including ethidium bromide, Lambda-[Ru(bpy)(2)eilatin]2+, and Delta-[Ru(bpy)(2)eilatin]2+ also inhibit HIV-1 gene expression in cell cultures (IC50 = 0.2-3 microM). These (and similar) results should facilitate the future discovery and implementation of anti-HIV drugs that are targeted to viral RNA sites. In addition, a deeper general understanding of RNA-small molecule recognition will assist in the effective targeting of other therapeutically important RNA sites.
Thermodynamics of aminoglycoside-rRNA recognition.
Pilch DS, Kaul M, Barbieri CM … +1 more , Kerrigan JE
Biopolymers · 2003 Sep · PMID 12925993 · Publisher ↗
2-Deoxystreptamine (2-DOS) aminoglycosides are a family of structurally related broad-spectrum antibiotics that are used widely in the treatment of infections caused by aerobic Gram-negative bacilli. Their antibiotic act...
2-Deoxystreptamine (2-DOS) aminoglycosides are a family of structurally related broad-spectrum antibiotics that are used widely in the treatment of infections caused by aerobic Gram-negative bacilli. Their antibiotic activities are ascribed to their abilities to bind a highly conserved A site in the 16 S rRNA of the 30 S ribosomal subunit and interfere with protein synthesis. The abilities of the 2-DOS aminoglycosides to recognize a specific subdomain of a large RNA molecule make these compounds archetypical models for RNA-targeting drugs. This article presents a series of calorimetric, spectroscopic, osmotic stress, and computational studies designed to evaluate the thermodynamics (DeltaG, DeltaH, DeltaS, DeltaCp) of aminoglycoside-rRNA interactions, as well as the hydration changes that accompany these interactions. In conjunction with the current structural database, the results of these studies provide important insights into the molecular forces that dictate and control the rRNA binding affinities and specificities of the aminoglycosides. Significantly, identification of these molecular driving forces [which include binding-linked drug protonation reactions, polyelectrolyte contributions from counterion release, conformational changes, hydration effects, and molecular interactions (e.g., hydrogen bonds and van der Waals interactions)], as well as the relative magnitudes of their contributions to the binding free energy, could not be achieved by consideration of structural data alone, highlighting the importance of acquiring both thermodynamic and structural information for developing a complete understanding of the drug-RNA binding process. The results presented here begin to establish a database that can be used to predict, over a range of conditions, the relative affinity of a given aminoglycoside or aminoglycoside mimetic for a targeted RNA site vs binding to potential competing secondary sites. This type of predictive capability is essential for establishment of a rational design approach to the development of new RNA-targeted drugs.
Structure and dynamics of nucleosomal DNA.
Muthurajan UM, Park YJ, Edayathumangalam RS … +4 more , Suto RK, Chakravarthy S, Dyer PN, Luger K
Biopolymers · 2003 Apr · PMID 12666179 · Publisher ↗
The last five years have seen exciting advances in our understanding of the structure of the nucleosome core particle, the basic repeating unit in all eukaryotic chromatin. A picture emerges in which nucleosomal DNA, whi...
The last five years have seen exciting advances in our understanding of the structure of the nucleosome core particle, the basic repeating unit in all eukaryotic chromatin. A picture emerges in which nucleosomal DNA, while distorted and compacted fivefold by tight interactions with the histone octamer core, is at the same time highly dynamic and adaptable. Here, we summarize the salient features from recent structural studies of nucleosome core particles (both published and unpublished) that concern the structure and dynamics of nucleosomal DNA, and the nature of protein-DNA interactions. Current mechanisms for chromatin remodeling and nucleosome sliding are discussed in light of new structural evidence. Finally, techniques to study nucleosome stability and ultimately dynamics are introduced.
Structures and interactions of the core histone tail domains.
Zheng C, Hayes JJ
Biopolymers · 2003 Apr · PMID 12666178 · Publisher ↗
The core histone tail domains are "master control switches" that help define the structural and functional characteristics of chromatin at many levels. The tails modulate DNA accessibility within the nucleosome, are esse...
The core histone tail domains are "master control switches" that help define the structural and functional characteristics of chromatin at many levels. The tails modulate DNA accessibility within the nucleosome, are essential for stable folding of oligonucleosome arrays into condensed chromatin fibers, and are important for fiber-fiber interactions involved in higher order structures. Many nuclear signaling pathways impinge upon the tail domains, resulting in posttranslational modifications that are likely to alter the charge, structure, and/or interactions of the core histone tails or to serve as targets for the binding of ancillary proteins or other enzymatic functions. However, currently we have only a marginal understanding of the molecular details of core histone tail conformations and contacts. Here we review data related to the structures and interactions of the core histone tail domains and how these domains and posttranslational modifications therein may define the structure and function of chromatin.
Atomistic protein folding simulations on the submillisecond time scale using worldwide distributed computing.
Pande VS, Baker I, Chapman J … +8 more , Elmer SP, Khaliq S, Larson SM, Rhee YM, Shirts MR, Snow CD, Sorin EJ, Zagrovic B
Biopolymers · 2003 Jan · PMID 12579582 · Publisher ↗
Atomistic simulations of protein folding have the potential to be a great complement to experimental studies, but have been severely limited by the time scales accessible with current computer hardware and algorithms. By...
Atomistic simulations of protein folding have the potential to be a great complement to experimental studies, but have been severely limited by the time scales accessible with current computer hardware and algorithms. By employing a worldwide distributed computing network of tens of thousands of PCs and algorithms designed to efficiently utilize this new many-processor, highly heterogeneous, loosely coupled distributed computing paradigm, we have been able to simulate hundreds of microseconds of atomistic molecular dynamics. This has allowed us to directly simulate the folding mechanism and to accurately predict the folding rate of several fast-folding proteins and polymers, including a nonbiological helix, polypeptide alpha-helices, a beta-hairpin, and a three-helix bundle protein from the villin headpiece. Our results demonstrate that one can reach the time scales needed to simulate fast folding using distributed computing, and that potential sets used to describe interatomic interactions are sufficiently accurate to reach the folded state with experimentally validated rates, at least for small proteins.
Structural models for dimerization of G-protein coupled receptors: the opioid receptor homodimers.
Filizola M, Weinstein H
Biopolymers · 2002 · PMID 12539260 · Publisher ↗
Among the most exciting functional features of G-protein coupled receptors (GPCRs) that are coming into focus lately are those relating to the role and structural characteristics of their oligomerization (mostly homo- an...
Among the most exciting functional features of G-protein coupled receptors (GPCRs) that are coming into focus lately are those relating to the role and structural characteristics of their oligomerization (mostly homo- and heterodimers). The structural underpinnings of these novel functional insights are still not clear, as current experimental techniques have not yet succeeded in identifying the dimerization interfaces between GPCR monomers. Two computational approaches have recently been designed in our lab to provide reasonable three-dimensional (3D) molecular models of the transmembrane (TM) regions of GPCR dimers based on a combination of the structural information of receptor monomers and analyses of correlated mutations in receptor families. The modeling of GPCR heterodimers has been described recently. We present here a related approach for modeling of GPCR homodimers that identifies the interfaces in the most likely configurations of the complexes. The approach is illustrated for the three cloned opioid receptor subtypes (OPRD, OPRM, and OPRK).
Synthetic peptides as cancer vaccines.
Sundaram R, Dakappagari NK, Kaumaya PT
Biopolymers · 2002 · PMID 12385038 · Publisher ↗
Effective cancer therapy or prevention has been the dream of physicians and scientists for many years. Although we are still very far from our ultimate goal of cancer prevention, significant milestones have been realized...
Effective cancer therapy or prevention has been the dream of physicians and scientists for many years. Although we are still very far from our ultimate goal of cancer prevention, significant milestones have been realized in terms of our knowledge base and understanding of the pathogenesis of cancerous cells and the involvement of the immune system against both self- and virus-associated tumor antigens. Immunotherapeutic strategies are now accepted to being superior in terms of the exquisite specificity that they offer in targeting only tumor cells as opposed to the existent chemotherapy or radiation therapy that is more general and invasive with many associated side effects. There are several immunotherapeutic strategies that are currently under investigation. This review primarily focuses on the significant advances made in the use of synthetic peptides in the development of subunit cancer vaccines. We have attempted to highlight some of the fundamental issues regarding antigen processing and presentation, Major Histocompatibility Complex (MHC) restriction, T-cell help, structural determinants in antibody recognition, and the use of these concepts in the rational design and delivery of peptide vaccines to elicit protective humoral and cell mediated immune responses. The recent use of costimulatory molecules and cytokines to augment immune responses also has been discussed along with the contributions of our laboratory to the field of synthetic peptide vaccine development.
Novel strategies for targeting the dimerization interface of HIV protease with cross-linked interfacial peptides.
Bowman MJ, Chmielewski J
Biopolymers · 2002 · PMID 12325162 · Publisher ↗
As the prevalence of AIDS continues to grow, and current therapeutic agents begin to lose efficacy, the need for alternative treatments to combat HIV has become significantly greater. Targeting the highly conserved dimer...
As the prevalence of AIDS continues to grow, and current therapeutic agents begin to lose efficacy, the need for alternative treatments to combat HIV has become significantly greater. Targeting the highly conserved dimerization interface of HIV protease (PR) with interfacial peptides has been shown to reduce the activity of the enzyme due to generation of inactive monomers. The potency of these peptide-based inhibitors has been dramatically increased by cross-linking the interfacial sequences derived from HIV PR. This review focuses on a variety of strategies to develop potent, low-molecular-weight dimerization inhibitors of HIV PR.
Discovery of nonpeptide, peptidomimetic peptidase inhibitors that target alternate enzyme active site conformations.
Rich DH, Bursavich MG, Estiarte MA
Biopolymers · 2002 · PMID 12325161 · Publisher ↗
Structure-generating programs provide rational methods to rapidly design novel scaffolds targeting the biologic receptor of choice. Recent research has demonstrated proteins equilibrate between families of conformations...
Structure-generating programs provide rational methods to rapidly design novel scaffolds targeting the biologic receptor of choice. Recent research has demonstrated proteins equilibrate between families of conformations (ensembles) for which drug design may target. New methods are currently being developed utilizing structure-generating programs to target alternate enzyme conformations in an attempt to overcome the challenge of developing therapeutically useful molecules. These new methods provide the potential to overcome bioavailability problems encountered with peptide and peptide-like molecules by identifying novel small molecule scaffolds.
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