Rafal Slusarz

University of Gdansk | UG · Faculty of Chemistry

We present the results for CAPRI Round 54, the 5th joint CASP‐CAPRI protein assembly prediction challenge. The Round offered 37 targets, including 14 homodimers, 3 homo‐trimers, 13 heterodimers including 3 antibody–antigen complexes, and 7 large assemblies. On average ~70 CASP and CAPRI predictor groups, including more than 20 automatics servers, s...

We present the results for CAPRI Round 54, the 5th joint CASP-CAPRI protein assembly prediction challenge. The Round offered 37 targets, including 14 homo-dimers, 3 homo-trimers, 13 hetero-dimers including 3 antibody-antigen complexes, and 7 large assemblies. On average ~70 CASP and CAPRI predictor groups, including more than 20 automatics servers,...

In this paper we report the improvements and extensions of the UNRES server ( https://unres-server.chem.ug.edu.pl ) for physics-based simulations with the coarse-grained UNRES model of polypeptide chains. The improvements include the replacement of the old code with the recently optimized one and adding the recent scale-consistent variant of the UN...

The article describes an NMR spectroscopy study of interactions between vancomycin and a muramyl pentapeptide in two complexes: vancomycin and a native muramyl pentapeptide ended with D-alanine (MPP-D-Ala), and vancomycin and a modified muramyl pentapeptide ended with D-serine (MPP-D-Ser). The measurements were made in a 9:1 mixture of H2O and D2O....

We present the results for CAPRI Round 50, the 4th joint CASP-CAPRI protein assembly prediction challenge. The Round comprised a total of 12 targets, including 6 dimers, 3 trimers, and 3 higher-order oligomers. Four of these were easy targets, for which good structural templates were available either for the full assembly, or for the main interface...

The UNited RESidue (UNRES) force field was tested in the 14th Community Wide Experiment on the Critical Assessment of Techniques for Protein Structure Prediction (CASP14), in which larger oligomeric and multimeric targets were present compared to previous editions. Three prediction modes were tested (i) ab initio (the UNRES group), (ii) contact-ass...

The synthesis of N-((methyl 5-deoxy-2,3-O-isopropylidene-β-D-ribofuranoside)-5-yl)ammonium salts are presented. To determine the effect of the nucleophile type and outgoing group on the quaternization reaction, selected aliphatic and heterocyclic aromatic amines reacted with: methyl 2,3-O-isopropylidene-5-O-tosyl-β-D-ribofuranoside or methyl 2,3-O-...

This paper presents synthesis of vancomycin derivatives modified with selected 1- and 2-aminoalditols to carboxylic function and 2,5-anhydro-D-mannose and D-talose to amino function of vancosamine via reductive alkylation. MIC and MBC of these derivatives were determined for reference strains of bacteria: Staphylococcus aureus ATCC 25923, ATCC 6538...

The method for protein-structure prediction, which combines the physics-based coarse-grained UNRES force field with knowledge-based modeling, has been developed further and tested in the 13th Community Wide Experiment on the Critical Assessment of Techniques for Protein Structure Prediction (CASP13). The method implements restraints from the consen...

The physics-based UNRES coarse-grained force field for the simulations of protein structure and dynamics has been extended to treat membrane proteins. The lipid bilayer has been modeled by introducing a continuous nonpolar phase with the water-interface region of appropriate thickness. The potentials for average electrostatic and correlation intera...

The recent NEWCT-9P version of the coarse-grained UNRES force field for proteins, with scale-consistent formulas for the local and correlation terms, has been tested in the CASP13 experiment of the blind-prediction of protein structure, in the ab initio, contact-assisted, and data-assisted modes. Significant improvement of the performance has been...

Quaternary ammonium salts are a group of compounds with diverse biological properties, the most important of which are their antiviral, antibacterial, and antifungal activities. The quaternization reactions of 5'-O-tosyl derivatives of uridine and thymidine with triethylamine, trimethylamine, 4-(N,N-dimethylamino)pyridine, 2-methylpyridine, and pyr...

Every two years groups worldwide participate in the Critical Assessment of Protein Structure Prediction (CASP) experiment to blindly test the strengths and weaknesses of their computational methods. CASP has significantly advanced the field but many hurdles still remain, which may require new ideas and collaborations. In 2012 a web-based effort cal...

Knowledge-based methods are, at present, the most effective ones for the prediction of protein structures; however, their results heavily depend on the similarity of a target sequence to those of proteins with known structures. On the other hand, the physics-based methods, although still less accurate and more expensive to execute, are independent...

Synthesis of 1,6-anhydro sugars is well known in literature. The dioxolane ring exhibits at least two types of properties. It can be used as a protecting group and reaction site. This work discusses the cleavage of the 1,6-anhydro ring of muramic acid derivatives. To induce the opening of the dioxolane ring in 1,6-anhydro-D-glucose derivatives thre...

Computational investigations were performed to examine the effects of the addition of 2-acetamido-2-deoxy-β-D-galactopyranosylamine or 1-amino-1-deoxy-D-glucitol connected to the C-terminus of vancomycin with different linkers. The purpose of this modification was to find more effective vancomycin derivatives by providing alternative interactions b...

Participating as the Cornell-Gdansk group, we have used our physics-based coarse-grained UNited RESidue (UNRES) force field to predict protein structure in the 11th Community Wide Exercise on the Critical Assessment of Techniques for Protein Structure Prediction (CASP11). Our methodology involved extensive multiplexed replica exchange simulations o...

Solid phase peptide synthesis (SPPS) of two selected muramyl pentapeptide derivatives is described. The simplicity of removing the protecting groups via one-step deprotection and cleavage from the resin is the biggest advantage of SPPS. Using this method, two muramyl pentapeptide derivatives, D-MurN3-L-Ala-D-iGlu-L-Lys-D-Ala-D-Ser (5) and D-MurN3-L...

Trypsin inhibitor SFTI-1 is the smallest and the most potent among BBI inhibitors. It is also an interesting object for SAR studies since it is cyclic 14 amino acid molecule which additionally contains disulfide bridge. We showed that elimination of head-to-tail cycliztion did not influence its activity. Moreover peptoid monomers of Nlys and Nphe i...

A unified coarse-grained model of three major classes of biological molecules—proteins, nucleic acids, and polysaccharides—has been developed. It is based on the observations that the repeated units of biopolymers (peptide groups, nucleic acid bases, sugar rings) are highly polar and their charge distributions can be represented crudely as point mu...

Proper understanding of the mechanisms of binding to Gram-positive bacteria cell wall layers-especially to the peptidoglycan (PG) layer, seems to be crucial for proper development of new drug candidates which are effective against these bacteria. In this work we have constructed two different models of the Gram-positive bacteria PG layer: the layer...

Significance With the example of the coarse-grained United Residue model of polypeptide chains, this paper demonstrates that the physics-based approach for protein-structure prediction can lead to exceptionally good results when correct domain packing is an issue, even for a highly homologous target. The reason for this is probably that emphasis is...

Vasopressin and oxytocin receptors belong to the superfamily of G protein-coupled receptors and play an important role in many physiological functions. They are also involved in a number of pathological conditions being important drug targets. In this work, four vasopressin analogues substituted at position 2 with 3,3'-diphenylalanine have been doc...

Six complexes of vancomycin and peptidoglycan precursors were studied via molecular dynamics simulations. The interactions between the antibiotic and peptidoglycan fragments were identified and described in detail. All six studied modifications of the peptidoglycan precursor resulted in a weakening of the interaction with vancomycin when comparing...

In this paper we use NMR spectroscopy and molecular modeling to examine four vasopressin analogues substituted with bulky 3,3'-diphenylalanine (Dpa) enantiomers: [Mpa(1),Dpa(2),Val(4),D-Arg(8)]VP (I), [Mpa(1),D-Dpa(2),Val(4),D-Arg(8)]VP (II), [D-Dpa(2),D-Arg(8)]VP (III) and [Mpa(1),D-Dpa(2)]AVP (IV). All the peptides exhibit a strong and prolonged...

In this work, the receptor-bound conformation of nine vasopressin (CYFQNCPRG-NH2, AVP) analogs substituted in positions 2 or 3 with 2-aminoindane-2-carboxylic acid have been investigated using molecular modeling methods. The synthesis and functional assays of the analogs have been recently described. For comparison, the molecular dynamics of the se...

The Escherichia coli heat shock protein ClpB, a member of the Hsp100 family, plays a crucial role in cellular thermotolerance. In co-operation with the Hsp70 chaperone system, it is able to solubilize proteins aggregated by heat shock conditions and refold them into the native state in an ATP-dependent way. It was established that the mechanism of...

The role of the internal water molecules in vasopressin and oxytocin receptors has been investigated via molecular dynamics simulations in hydrated membrane model. Several water molecules have been identified within the binding pockets of receptors, where they interact with the conserved residues. In all unliganded receptors, the water molecules bo...

In the Arginine Vasopressin (CYFQNCPRG–NH2, AVP) molecule, the disulfide bond between Cys1 and Cys6 forms a 20-membered ring crucial for AVP activity. The activity could be enhanced by restraining the AVP structure with additional cyclic moiety. To reduce AVP conformational flexibility, a standard link has now been added between residues at positio...

In this study, four cyclic vasopressin (CYFQNCPRG-NH(2), AVP) analogues substituted at positions 2 and 3 with four combinations of enantiomers of N-methylphenylalanine have been investigated. Three-dimensional structures of analogues have been formerly determined using NMR spectroscopy in dimethyl sulfoxide. Three-dimensional models of the vasopres...

The vasopressin V2 receptor (V2R) belongs to the Class A G protein–coupled receptors (GPCRs). V2R is expressed in the renal collecting duct (CD), where it mediates the antidiuretic action of the neurohypophyseal hormone arginine vasopressin (CYFQNCPRG-NH2, AVP). Desmopressin ([1-deamino, 8-D]AVP, dDAVP) is strong selective V2R agonist with negligib...

The neurohypophyseal hormone oxytocin (CYIQNCPLG-NH(2), OT) is involved in the control of labor, secretion of milk and many social and behavioral functions via interaction with its receptors (OTR) located in the uterus, mammary glands and peripheral tissues, respectively. In this paper we propose the interactions responsible for OT binding and sele...

Vasopressin (CYFQNCPRG-NH(2), AVP) is a semicyclic endogenous peptide, which exerts a variety of biological effects in mammals. The main physiological roles of AVP are the regulation of water balance and the control of blood pressure and adrenocorticotropin hormone (ACTH) secretion, mediated via three different subtypes of vasopressin receptors: V1...

Conformational studies of three agonists of V(2) receptor modified with 1-aminocyclohexane-1-carboxylic acid (Acc), [Acc(2),DArg(8)]VP, [Acc(3)]AVP and [Cpa(1),Acc(3)]AVP, using 2D NMR and theoretical calculations are presented in this paper. It is believed that alpha,alpha-disubstituted amino acids, such as Acc, affect the formation of either 3(10...

The solution conformation of vasopressin analogues, modified at positions 2 and 3 with N-methylphenylalanine or its enantiomer, [D-MePhe2,MePhe3]AVP and [MePhe2,D-MePhe3]AVP, were studied by 2D NMR spectroscopy in H2O/D2O and theoretical calculations (EDMC/ANALYZE). In the case of [MePhe2,D-MePhe3]AVP, the synthesis afforded two products, A and B,...

A model believed to be representative for activated class A G protein-coupled receptors is proposed. It consists of rhodopsin and the transducin α C-terminal peptide [Gtα(338–350)] docked to it. The model utilizes the resolved interactions/distances, found to be essential in the activated rhodopsin (RD*) and the structure of Gtα(338–350) that is kn...

The solution conformations of two potent antagonists of bradykinin (Arg1-Pro2-Pro3-Gly4-Phe5-Ser6-Pro7-Phe8-Arg9), [Aca(-1),DArg0,Hyp3,Thi5,DPhe7,(N-Bzl)Gly8]BK (1) and [Aaa(-1),DArg0,Hyp3,Thi5,(2-DNal)7,Thi8]BK (2), were studied by using 2D NMR spectroscopy in DMSO-d6 and molecular dynamics simulations. The NMR spectra of peptide 1 reveals the exi...

Growing evidence that rhodopsin (RD) and related G protein-coupled receptors form functional dimers/oligomers, followed by direct proof (using atomic force microscopy) that in the retina disc membrane RD associates into a paracrystalline network of rows of dimers, need models of the RD-transducin (Gt) complex that would envision an optimal RD dimer...

The nonapeptide hormone oxytocin CYIQNCPLG-NH2 (OT) controls birth, lactation and other physiological functions in the mammals via stimulation of its receptor (OTR), a member of Class A G protein-coupled receptors (GPCRs). OT is structurally akin to arginine vasopressin ([F2,R8]OT, AVP) involved, among other things, in the increase of blood pressur...

The aim of our research was to get insight into the molecular mechanism of binding atosiban, a strong selective oxytocin (OT) antagonist by OT receptor (OTR) versus vasopressin V1a and V2 receptors (V1aR and V2R, respectively). The docking of ligand and interaction with receptor are dynamic events and Molecular Dynamics (MD) seems to be a proper to...

A model for interaction of class A G protein-coupled receptor with the G protein G(alpha) subunit is proposed using the rhodopsin-transducin (RD/Gt) prototype. The model combines the resolved interactions/distances, essential in the active RD*/Gt system, with the structure of Gt(alpha) C-terminal peptide bound to RD* while stabilizing it. Assuming...

G protein-coupled receptors relay diverse extracellular signals into cells via a common mechanism, involving activation of cytosol G proteins. The mechanism underlies the actions of approximately 50% of all drugs. In this work, we focus on simulating three protein-ligand complexes of the neurohypophyseal hormone analog 4-OH-phenylacetyl- D-Y(Me)FQN...

In this study the interaction of seven new analogs of arginine vasopressin (AVP) substituted in position 2 or 3 with 1-aminocyclohexanecarboxylic acid (Acc) with the vasopressin (VP) and oxytocin (OT) receptors (V1aR, V2R and OTR) is described. All peptides were synthesized and tested in bioassays for pressor and antidiuretic activities. Also their...

The neurohypophyseal nonapeptide hormone oxytocin (OT) is the strongest uterotonic substance known and is responsible for the initiation of labor. Conversely, oxytocin antagonists blocking uterine OT receptor can suppress uterus contraction. In this paper we describe a computer simulated docking pertinent to affinity of an oxytocin antagonist atosi...

The nonapeptide hormones arginine vasopressin (CYFQNCPRG-NH2, AVP) and oxytocin (CYIQNCPLG-NH2, OT), control many essential functions in mammals. Their main activities include the urine concentration (via stimulation of AVP V2 receptors, V2R, in the kidneys), blood pressure regulation (via stimulation of vascular V1a AVP receptors, V1aR), ACTH cont...

Hepta-helical transmembrane receptors transducing diverse external signals to cells via activation of heterotrimeric GTP-binding proteins (G-proteins), estimated to occupy over 3% of our genome [1] and to mediate actions of 60% of drugs [2], had long been resistant to structure determination. Thus, the first 3D structure of a G protein-coupled rece...

G protein-coupled receptors (GPCRs) transducing diverse external signals to cells via activation of heterotrimeric GTP-binding (G) proteins, estimated to mediate actions of 60% of drugs, had been resistant to structure determination until summer 2000. The first atomic-resolution experimental structure of a GPCR, that of dark (inactive) rhodopsin, t...

Molecular docking simulations are now fast developing area of research. In this work we describe an effective procedure of preparation of the receptor-ligand complexes. The amino-acid residues involved in ligand binding were identified and described.

Introduction of the naphthylalanine residue into either position 3 of arginine vasopressin (AVP), or its analogs results in peptides with interesting pharmacological properties. The single substituted analog of AVP with L-2-Nal in position 3 causes moderate antiduretic activity, whereas [Mpa1, (L-1-Nal)3, (D-Arg)8] VP and [Mpa1, (L-2-Nal)3, (D-Arg)...