@article {567, title = {Integrative modeling of diverse protein-peptide systems using CABS-dock}, journal = {PLoS Comput Biol.}, volume = {5;19(7)}, year = {2023}, pages = {e1011275}, abstract = {The CABS model can be applied to a wide range of protein-protein and protein-peptide molecular modeling tasks, such as simulating folding pathways, predicting structures, docking, and analyzing the structural dynamics of molecular complexes. In this work, we use the CABS-dock tool in two diverse modeling tasks: 1) predicting the structures of amyloid protofilaments and 2) identifying cleavage sites in the peptide substrates of proteolytic enzymes. In the first case, simulations of the simultaneous docking of amyloidogenic peptides indicated that the CABS model can accurately predict the structures of amyloid protofilaments which have an in-register parallel architecture. Scoring based on a combination of symmetry criteria and estimated interaction energy values for bound monomers enables the identification of protofilament models that closely match their experimental structures for 5 out of 6 analyzed systems. For the second task, it has been shown that CABS-dock coarse-grained docking simulations can be used to identify the positions of cleavage sites in the peptide substrates of proteolytic enzymes. The cleavage site position was correctly identified for 12 out of 15 analyzed peptides. When combined with sequence-based methods, these docking simulations may lead to an efficient way of predicting cleavage sites in degraded proteins. The method also provides the atomic structures of enzyme-substrate complexes, which can give insights into enzyme-substrate interactions that are crucial for the design of new potent inhibitors.}, author = {Wojciech Pulawski and Michal Kolinski and Andrzej Koli{\'n}ski} } @article {566, title = {Molecular Dynamics Scoring of Protein{\textendash}Peptide Models Derived from Coarse-Grained Docking}, journal = {Molecules}, volume = {26(11)}, year = {2021}, chapter = {3293}, abstract = {One of the major challenges in the computational prediction of protein{\textendash}peptide complexes is the scoring of predicted models. Usually, it is very difficult to find the most accurate solutions out of the vast number of sometimes very different and potentially plausible predictions. In this work, we tested the protocol for Molecular Dynamics (MD)-based scoring of protein{\textendash}peptide complex models obtained from coarse-grained (CG) docking simulations. In the first step of the scoring procedure, all models generated by CABS-dock were reconstructed starting from their original C-alpha trace representations to all-atom (AA) structures. The second step included geometry optimization of the reconstructed complexes followed by model scoring based on receptor{\textendash}ligand interaction energy estimated from short MD simulations in explicit water. We used two well-known AA MD force fields, CHARMM and AMBER, and a CG MARTINI force field. Scoring results for 66 different protein{\textendash}peptide complexes show that the proposed MD-based scoring approach can be used to identify protein{\textendash}peptide models of high accuracy. The results also indicate that the scoring accuracy may be significantly affected by the quality of the reconstructed protein receptor structures.}, issn = {1420-3049}, doi = {10.3390/molecules26113293}, url = {https://www.mdpi.com/1420-3049/26/11/3293}, author = {Mateusz Zalewski and Sebastian Kmiecik and Michal Kolinski} } @article {561, title = {Docking of peptides to GPCRs using a combination of CABS-dock with FlexPepDock refinement}, journal = {Briefings in Bioinformatics}, year = {2020}, month = {06}, abstract = {The structural description of peptide ligands bound to G protein-coupled receptors (GPCRs) is important for the discovery of new drugs and deeper understanding of the molecular mechanisms of life. Here we describe a three-stage protocol for the molecular docking of peptides to GPCRs using a set of different programs: (1) CABS-dock for docking fully flexible peptides; (2) PD2 method for the reconstruction of atomistic structures from C-alpha traces provided by CABS-dock and (3) Rosetta FlexPepDock for the refinement of protein{\textendash}peptide complex structures and model scoring. We evaluated the proposed protocol on the set of seven different GPCR{\textendash}peptide complexes (including one containing a cyclic peptide), for which crystallographic structures are available. We show that CABS-dock produces high resolution models in the sets of top-scored models. These sets of models, after reconstruction to all-atom representation, can be further improved by Rosetta high-resolution refinement and/or minimization, leading in most of the cases to sub-Angstrom accuracy in terms of interface root-mean-square-deviation measure.}, issn = {1477-4054}, doi = {10.1093/bib/bbaa109}, url = {https://doi.org/10.1093/bib/bbaa109}, author = {Aleksandra E. Badaczewska-Dawid and Sebastian Kmiecik and Michal Kolinski} } @article {553, title = {Flexible docking of peptides to proteins using CABS-dock}, journal = {Protein Science, 29:211-222}, year = {2020}, abstract = {Molecular docking of peptides to proteins can be a useful tool in the exploration of the possible peptide binding sites and poses. CABS-dock is a method for protein{\textendash}peptide docking that features significant conformational flexibility of both the peptide and the protein molecules during the peptide search for a binding site. The CABS-dock has been made available as a web server and a standalone package. The web server is an easy to use tool with a simple web interface. The standalone package is a command-line program dedicated to professional users. It offers a number of advanced features, analysis tools and support for large-sized systems. In this article, we outline the current status of the CABS-dock method, its recent developments, applications, and challenges ahead.}, keywords = {molecular modeling, peptide drugs, peptide therapeutics, protein{\textendash}peptide complex, protein{\textendash}peptide interactions, structure prediction}, doi = {10.1002/pro.3771}, url = {https://onlinelibrary.wiley.com/doi/abs/10.1002/pro.3771}, author = {Mateusz Kurcinski and Aleksandra E. Badaczewska-Dawid and Michal Kolinski and Andrzej Koli{\'n}ski and Sebastian Kmiecik} } @inbook {539, title = {Protein Dynamics Simulations Using Coarse-Grained Models}, booktitle = {Computational Methods to Study the Structure and Dynamics of Biomolecules and Biomolecular Processes: From Bioinformatics to Molecular Quantum Mechanics}, year = {2019}, pages = {61{\textendash}87}, publisher = {Springer International Publishing}, organization = {Springer International Publishing}, edition = {Adam Liwo}, abstract = {Simulations of protein dynamics may work on different levels of molecular detail. The levels of simplification (coarse-graining) may concern different simulation aspects, including protein representation, interaction schemes or models of molecular motion. So-called coarse-grained (CG) models offer many advantages, unreachable by classical simulation tools, as demonstrated in numerous studies of protein dynamics. Followed by a brief introduction, we present example applications of CG models for efficient predictions of biophysical mechanisms. We discuss the following topics: mechanisms of chaperonin action, mechanical properties of proteins and their complexes, membrane proteinsMembrane proteins and lipids, protein-protein interactions and intrinsically unfolded proteins. These areas illustrate the opportunities for practical applications of CG simulations.}, isbn = {978-3-319-95843-9}, doi = {10.1007/978-3-319-95843-9_3}, url = {https://doi.org/10.1007/978-3-319-95843-9_3}, author = {Sebastian Kmiecik and Jacek Wabik and Michal Kolinski and Maksim Kouza and Andrzej Koli{\'n}ski} } @inbook {540, title = {Protein Structure Prediction Using Coarse-Grained Models}, booktitle = {Computational Methods to Study the Structure and Dynamics of Biomolecules and Biomolecular Processes: From Bioinformatics to Molecular Quantum Mechanics}, year = {2019}, pages = {27{\textendash}59}, publisher = {Springer International Publishing}, organization = {Springer International Publishing}, abstract = {The knowledge of the three-dimensional structure of proteins is crucial for understanding many important biological processes. Most of the biologically relevant protein systems are too large for classical, atomistic molecular modeling tools. In such cases, coarse-grained (CG) models offer various opportunities for efficient conformational sampling and thus prediction of the three-dimensional structure. A variety of CG models have been proposed, each based on a similar framework consisting of a set of conceptual components such as protein representation, force field, sampling, etc. In this chapter we discuss these components, highlighting ideas which have proven to be the most successful. As CG methods are usually part of multistage procedures, we also describe approaches used for the incorporation of homology data and all-atom reconstruction methods.}, isbn = {978-3-319-95843-9}, doi = {10.1007/978-3-319-95843-9_2}, url = {https://doi.org/10.1007/978-3-319-95843-9_2}, author = {Maciej Blaszczyk and Dominik Gront and Sebastian Kmiecik and Mateusz Kurcinski and Michal Kolinski and Maciej Ciemny and Katarzyna Ziolkowska and Marta Panek and Andrzej Koli{\'n}ski} } @article {537, title = {Design and synthesis of novel 1H-tetrazol-5-amine based potent antimicrobial agents: DNA topoisomerase IV and gyrase affinity evaluation supported by molecular docking studies}, journal = {European Journal of Medicinal Chemistry}, volume = {156}, year = {2018}, pages = {631 - 640}, abstract = {A total of 14 of 1,5-disubstituted tetrazole derivatives were prepared by reacting appropriate thiourea and sodium azide in the presence of mercury (II) chloride and triethylamine. All compounds were evaluated in\ vitro for their antimicrobial activity. Derivatives 10 and 11 showed the highest inhibition against Gram-positive and Gram-negative strains (standard and hospital strains). The observed minimal inhibitory concentrations values were in the range of 1{\textendash}208 μM (0.25{\textendash}64 μg/ml). Inhibitory activity of 1,5-tetrazole derivatives 10 and 11 against gyrase and topoisomerase IV isolated from S.\ aureus was studied. Evaluation was supported by molecular docking studies for all synthesized derivatives and reference ciprofloxacin. Moreover, selected tetrazoles (2, 3, 5, 6, 8, 9, 10 and 11) were evaluated for their cytotoxicity. All tested compounds are non-cytotoxic against HaCaT and A549 cells (CC50 <= 60 μM).}, keywords = {1H-tetrazol-5-amine, Antimicrobial activity, Cytotoxicity, DNA gyrase, molecular docking, Topoisomerase type IV}, issn = {0223-5234}, doi = {https://doi.org/10.1016/j.ejmech.2018.07.041}, url = {http://www.sciencedirect.com/science/article/pii/S022352341830597X}, author = {Daniel Szulczyk and Micha{\l} A. Dobrowolski and Piotr Roszkowski and Anna Bielenica and Joanna Stefa{\'n}ska and Michal Kolinski and Sebastian Kmiecik and Micha{\l} J{\'o}{\'z}wiak and Ma{\l}gorzata Wrzosek and Wioletta Olejarz and Marta Struga} } @article {473, title = {5-HT2 receptor affinity, docking studies and pharmacological evaluation of a series of 1,3-disubstituted thiourea derivatives}, journal = {European Journal of Medicinal Chemistry}, volume = {116}, year = {2016}, pages = {173{\textendash}186}, abstract = {A series of 10 thiourea derivatives have been synthesized by the reaction of aromatic amine with a substituted aryl (compounds 1-3, 6-8) and alkylphenyl (4, 5, 9, 10) isothiocyanates. Their in vitro and in vivo pharmacological properties were studied. Among the evaluated compounds, two displayed very high affinity for the 5-HT2A receptor (1 {\textendash} 0.043 nM and 5 {\textendash} 0.6 nM), being selective over the 5-HT2C receptor. Derivatives 3, 5, 9, 10 by 70- 89 \% diminished L-5-HTP-induced head twitch episodes. Compounds 1 and 5 as the 5-HT2A receptor antagonists produced a dose-dependent decrease in the number of DOI-elicited HTR. Compounds 1-5 strongly reduced amphetamine-evoked hyperactivity in rodents. In another test, 1 and 2 caused hyperthermia in mice, whereas 9 and 10 led to hypothermia. Antinociceptive and anticonvulsant properties of selected derivatives were demonstrated. Molecular docking studies using a homology model of 5-HT2A revealed a significant role of hydrogen bonds between both thiourea NH groups and Asp155/Tyr370 residues, as well as Pi-Pi interaction with Phe339.}, author = {Anna Bielenica and Ewa Kedzierska and Michal Kolinski and Sebastian Kmiecik and Andrzej Koli{\'n}ski and Ferdinando Fiorino and Beatrice Severino and Elisa Magli and Ilaria Rossi and Paola Massarelli and Anna E Kozio{\l} and Aleksandra Sawczenko and Marta Struga} } @article {482, title = {Coarse-Grained Protein Models and Their Applications}, journal = {Chemical Reviews}, volume = {116}, year = {2016}, pages = {7898{\textendash}7936}, abstract = {The traditional computational modeling of protein structure, dynamics and interactions remains difficult for many protein systems. It is mostly due to the size of protein conformational spaces and required simulation timescales that are still too large to be studied in atomistic detail. Lowering the level of protein representation from all-atom to coarse-grained opens up new possibilities for studying protein systems. In this review we provide an overview of coarse-grained models focusing on their design, including choices of representation, models of energy functions, sampling of conformational space, and applications in the modeling of protein structure, dynamics and interactions. A more detailed description is given for applications of coarse-grained models suitable for efficient combinations with all-atom simulations in multiscale modeling strategies.}, doi = {10.1021/acs.chemrev.6b00163}, url = {https://pubs.acs.org/doi/10.1021/acs.chemrev.6b00163}, author = {Sebastian Kmiecik and Dominik Gront and Michal Kolinski and Lukasz Wieteska and Aleksandra Dawid and Andrzej Koli{\'n}ski} } @article {493, title = {Coarse-grained simulations of membrane insertion and folding of small helical proteins using CABS model}, journal = {Journal of Chemical Information and Modeling}, volume = {56}, year = {2016}, pages = {2207{\textendash}2215}, abstract = {The CABS coarse-grained model is a well-established tool for modeling globular proteins (predicting their structure, dynamics and interactions). Here we introduce an extension of CABS representation and force field (CABS-membrane) to the modeling of the effect of biological membrane environment on the structure of membrane proteins. We validate the CABS-membrane model in folding simulations of 10 short helical membrane proteins not using any knowledge about their structure. The simulations start from random protein conformations placed outside the membrane environment and allow for full flexibility of the modeled proteins during their spontaneous insertion into the membrane. In the resulting trajectories, we have found models close to the experimental membrane structures. We also attempted to select the correctly folded models using simple filtering followed by structural clustering combined with reconstruction to all-atom representation and all-atom scoring. In conclusion, the CABS-membrane model is a promising approach for further development towards modeling of large protein-membrane systems.}, doi = {10.1021/acs.jcim.6b00350}, url = {https://pubs.acs.org/doi/abs/10.1021/acs.jcim.6b00350}, author = {Wojciech Pulawski and Michal Jamroz and Michal Kolinski and Andrzej Koli{\'n}ski and Sebastian Kmiecik} } @inbook {347, title = {Coarse-Grained Modeling of Protein Dynamics}, booktitle = {Computational Methods to Study the Structure and Dynamics of Biomolecules and Biomolecular Processes, Springer Series in Bio-/Neuroinformatics, Adam Liwo, Ed.}, volume = {1}, year = {2014}, pages = {55-79}, publisher = {Springer Berlin Heidelberg}, organization = {Springer Berlin Heidelberg}, abstract = {Simulations of protein dynamics may work on different levels of molecular detail. The levels of simplification (coarse-graining) can range from very low to atomic resolution and may concern different simulation aspects (including protein representation, interaction schemes or models of molecular motion). So-called coarse-grained (CG) models offer many advantages, unreachable by classical simulation tools, as demonstrated in numerous studies of protein dynamics. Followed by a brief introduction, we present example applications of CG models for efficient predictions of biophysical mechanisms. We discuss the following topics: mechanisms of chaperonin action, mechanical properties of proteins, membrane proteins, protein-protein interactions and intrinsically unfolded proteins. Presently, these areas represent emerging application fields of CG simulation models.}, keywords = {coarse-grained modeling, protein dynamics}, doi = {10.1007/978-3-642-28554-7_3}, author = {Sebastian Kmiecik and Jacek Wabik and Michal Kolinski and Maksim Kouza and Andrzej Koli{\'n}ski} } @article {401, title = {Structure prediction of the second extracellular loop in G-protein-coupled receptors}, journal = {Biophysical Journal}, volume = {106}, year = {2014}, pages = {2408{\textendash}2416}, abstract = {G protein-coupled receptors (GPCRs) play key roles in living organisms. Therefore it is important to determine their functional structures. The second extracellular loop (ECL2) is a functionally important region of GPCRs which poses significant challenge for computational structure prediction methods. In this work, we evaluated CABS, a well-established protein modeling tool for predicting ECL2 structure in thirteen GPCRs. The ECL2s (with between 13 and 34 residues) are predicted in an environment of other extracellular loops being fully flexible and the transmembrane domain fixed in its X-ray conformation. The modeling procedure utilized theoretical predictions of ECL2 secondary structure and experimental constraints on disulfide bridges. Our approach yielded ensembles of low-energy conformers and the most populated conformers that contained models close to the available X-ray structures. Predicted loop fragments resemble X-ray structures with comparable accuracy to those obtained by other state-of-the-art methods. Our results extend other studies by including newly crystallized GPCRs.}, author = {Sebastian Kmiecik and Michal Jamroz and Michal Kolinski} } @article {280, title = {Modelowanie Molekularne Bia{\l}ek B{\l}onowych (Molecular Modeling of Membrane Proteins)}, journal = {Na pograniczu chemii i biologii (At the Treshold of Chemistry and Biology) vol. XXVIII, H. Koroniak, J. Barciszewski eds, Wydawnictwo Naukowe UAM, Pozna{\'n}}, year = {2012}, pages = {223-238}, abstract = {Jednym z g{\l}{\'o}wnych cel{\'o}w wsp{\'o}{\l}czesnych bada{\'n} biomedycznych jest zrozumienie na poziomie molekularnym podstawowych proces{\'o}w odpowiedzialnych za prawid{\l}owe funkcjonowanie organizmu, a tak{\.z}e zachodz{\k a}cych w nim proces{\'o}w chorobotw{\'o}rczych. Kluczowym elementem wielu takich mechanizm{\'o}w s{\k a} bia{\l}ka b{\l}onowe (zwi{\k a}zane ze struktur{\k a} b{\l}on biologicznych). Szacuje si{\k e}, {\.z}e ponad 60\% cel{\'o}w dla nowych lek{\'o}w to bia{\l}ka b{\l}onowe [1]. Ich zr{\'o}{\.z}nicowana funkcjonalno{\'s}{\'c} przejawia si{\k e} w wielu aspektach {\.z}ycia kom{\'o}rkowego: utrzymuj{\k a} stabilno{\'s}{\'c} strukturaln{\k a} kom{\'o}rek, stanowi{\k a} wa{\.z}ny element kaskad sygnalizacyjnych jako receptory b{\l}onowe, wykazuj{\k a} aktywno{\'s}{\'c} katalityczn{\k a} wyst{\k e}puj{\k a}c w roli enzym{\'o}w, s{\k a} odpowiedzialne za transport molekularny ma{\l}ych cz{\k a}steczek przez b{\l}on{\k e} lipidow{\k a} jako kana{\l}y, transportery oraz pompy jonowe. Na szczeg{\'o}ln{\k a} uwag{\k e} zas{\l}uguje rodzina A podobnych do rodopsyny (ang. rhodopsin-like) receptor{\'o}w b{\l}onowych sprz{\k e}{\.z}onych z bia{\l}kami G (GPCR {\textendash} ang. G protein-coupled receptors), odpowiedzialnych mi{\k e}dzy innymi za kontrol{\k e} odczuwania b{\'o}lu (receptory opioidowe), ci{\'s}nienia t{\k e}tniczego (receptory adrenergiczne), proces widzenia (rodopsyna), czy odczuwanie smaku i zapachu. Ich wsp{\'o}ln{\k a} funkcj{\k a} jest przekazywanie oraz wzmacnianie specyficznych sygna{\l}{\'o}w docieraj{\k a}cych do wn{\k e}trza kom{\'o}rki z jej otoczenia. Mechanizm tego procesu rozpoczyna si{\k e} od zwi{\k a}zania cz{\k a}steczki sygna{\l}owej (liganda) przez zewn{\k a}trzkom{\'o}rkow{\k a} domen{\k e} receptora. Prowadzi to do zmian konformacyjnych w strukturze receptora umo{\.z}liwiaj{\k a}cych wi{\k a}zanie bia{\l}ek G po wewn{\k e}trznej stronie b{\l}ony oraz ich aktywacj{\k e}. Aktywowane bia{\l}ka G mog{\k a} nast{\k e}pnie przekaza{\'c} sygna{\l} do dalszych bia{\l}ek efektorowych zlokalizowanych we wn{\k e}trzu kom{\'o}rki, a tym samym zainicjowa{\'c} skomplikowane kaskady sygnalizacyjne. Pojedynczy receptor mo{\.z}e aktywowa{\'c} wiele bia{\l}ek G co prowadzi do znacznego wzmocnienia przekazywanego sygna{\l}u. Wszelkie nieprawid{\l}owo{\'s}ci wyst{\k e}puj{\k a}ce na dowolnym etapie przekazywania sygna{\l}u mog{\k a} doprowadzi{\'c} do zaburzenia fizjologii oraz inicjacji proces{\'o}w chorobotw{\'o}rczych [2,3]. Aby im przeciwdzia{\l}a{\'c}, niezwykle pomocna jest znajomo{\'s}{\'c} mechanizmu dzia{\l}ania danego receptora na poziomie molekularnym. Oznacza to konieczno{\'s}{\'c} znajomo{\'s}ci struktury receptora (z dok{\l}adno{\'s}ci{\k a} do po{\l}o{\.z}enia poszczeg{\'o}lnych atom{\'o}w), co jest pierwszym etapem w drodze do zrozumienia mechanizmu przeniesienia sygna{\l}u oraz stanowi punkt wyj{\'s}ciowy do projektowania nowych, bardziej skutecznych lek{\'o}w, kt{\'o}re b{\k e}d{\k a} selektywne wzgl{\k e}dem danego typu receptora. W por{\'o}wnaniu do bia{\l}ek globularnych, eksperymentalne otrzymywanie struktury bia{\l}ek b{\l}onowych jest du{\.z}o bardziej skomplikowanym zadaniem, cz{\k e}sto niewykonalnym przy obecnym stanie wiedzy. Jest to spowodowane problemami pojawiaj{\k a}cymi si{\k e} podczas procesu krystalizacji bia{\l}ek b{\l}onowych (du{\.z}a powierzchnia hydrofobowa, {\'s}rodowisko b{\l}ony, niestabilno{\'s}{\'c} konformacyjna, niski poziom ekspresji) [4,5]. Pomimo, {\.z}e bia{\l}ka b{\l}onowe stanowi{\k a} oko{\l}o jedn{\k a} trzeci{\k a} wszystkich bia{\l}ek obecnych w ludzkim genomie [6], zaledwie oko{\l}o 1\% znanych struktur przestrzennych bia{\l}ek nale{\.z}y do przedstawicieli tej rodziny. Nieliczne, dost{\k e}pne struktury krystalograficzne otrzymane w specyficznych warunkach (bez b{\l}ony biologicznej) s{\k a} niezwykle pomocne w badaniach mechanizmu dzia{\l}ania tych bia{\l}ek. Bior{\k a}c pod uwag{\k e} ograniczenia metod eksperymentalnych oraz ogromne znaczenie bia{\l}ek b{\l}onowych dla przemys{\l}u farmakologicznego, zastosowanie metod teoretycznych do badania ich struktury, dynamiki i funkcji jest bardzo obiecuj{\k a}c{\k a} alternatyw{\k a}.}, author = {Aleksandra Dawid and Michal Kolinski and Andrzej Koli{\'n}ski and Sebastian Kmiecik} }