BazTech - Yadda

1

Computational Intelligence for Life Sciences

Besozzi Daniela, Manzoni Luca, Nobile Marco S., Spolaor Simone, Castelli Mauro, Vanneschi Leonardo, Cazzaniga Paolo, Ruberto Stefano, Rundo Leonardo, Tangherloni Andrea

Fundamenta Informaticae

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2020

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Vol. 171, nr 1-4

57--80

EN

Computational Intelligence (CI) is a computer science discipline encompassing the theory, design, development and application of biologically and linguistically derived computational paradigms. Traditionally, the main elements of CI are Evolutionary Computation, Swarm Intelligence, Fuzzy Logic, and Neural Networks. CI aims at proposing new algorithms able to solve complex computational problems by taking inspiration from natural phenomena. In an intriguing turn of events, these nature-inspired methods have been widely adopted to investigate a plethora of problems related to nature itself. In this paper we present a variety of CI methods applied to three problems in life sciences, highlighting their effectiveness: we describe how protein folding can be faced by exploiting Genetic Programming, the inference of haplotypes can be tackled using Genetic Algorithms, and the estimation of biochemical kinetic parameters can be performed by means of Swarm Intelligence. We show that CI methods can generate very high quality solutions, providing a sound methodology to solve complex optimization problems in life sciences.

2

Backbone dihedral angles prediction servers for protein early-stage structure prediction

Smolarczyk Tomasz, Stapor Katarzyna, Roterman-Konieczna Irena

Bio-Algorithms and Med-Systems

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2019

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Vol. 15, no. 4

art. no. 20190034

EN

Three-dimensional protein structure prediction is an important task in science at the intersection of biology, chemistry, and informatics, and it is crucial for determining the protein function. In the two-stage protein folding model, based on an early- and late-stage intermediates, we propose to use state-of-the-art secondary structure prediction servers for backbone dihedral angles prediction and devise an early-stage structure. Early-stage structures are used as a starting point for protein folding simulations, and any errors in this stage affect the final predictions. We have shown that modern secondary structure prediction servers could increase the accuracy of early-stage predictions compared to previously reported models.

3

Approximation Algorithms for Three Dimensional Protein Folding

Shaw D. L., Karmaker S., Islam A. S. M. S, Rahman M. S.

Fundamenta Informaticae

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2018

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Vol. 163, nr 4

375--393

EN

Predicting the secondary structure of a protein using a lattice model is one of the most studied computational problems in bioinformatics. Here the secondary structure or three dimensional structure of a protein is predicted from its amino acid sequence. The secondary structure refers to the local sub-structures of a protein. Simplified energy models have been proposed in the literature on the basis of interaction of amino acid residues in proteins. We focus on a well researched model known as the Hydrophobic-Polar (HP) energy model. In this paper, we propose the hexagonal prism lattice with diagonals that can overcome the problems of other lattice structures, e.g., parity problem. We give two approximation algorithms for protein folding on this lattice using HP model. Our first algorithm leads us to a similar structure of helix structure that is commonly found in a protein structure. This motivates us to propose the next algorithm with a better approximation ratio. Finally, we analyze the algorithms on the basis of intensity of the chemical forces along the different types of edges of hexagonal prism lattice with diagonals.

4

Chain-chain complexation and heme binding in haemoglobin with respect to the hydrophobic core structure

Ptak M., Banach M., Wiśniowski Z., Konieczny L., Roterman I.

Bio-Algorithms and Med-Systems

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2017

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Vol. 13, no. 4

179--185

EN

Heme binding by proteins and protein-protein complexation are the processes strongly related to the biological activity of proteins. The mechanism of these processes has not been still recognised. These phenomena are presented using haemoglobin as the example. Half of the mature haemoglobin (one α-chain and one β-chain) treated as a dissociation step in haemoglobin degradation reveals a specific change in heme binding after dissociation. This phenomenon is the object of analysis that interprets the structure of both complexes (tetramer and dimer) with respect to their hydrophobic core structure. The results suggest the higher stability of the complex in the form of one α-chain and one β-chain with respect to the hydrophobic core.

5

Treatment of disulfide bonds in coarse-grained UNRES force field

Krupa P.

TASK Quarterly : scientific bulletin of Academic Computer Centre in Gdansk

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2016

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Vol. 20, No 4

393--398

EN

Disulfide bonds, despite the advances of the computational methods, are underrepresented in theoretical chemistry and the role of disulfide bonds is of ten diminished in bioinformatical studies. Most of the molecular modeling tools do not allow studying the process of disulfide bond formation and breaking, which is equally important as the sole presence of disulfide bonds in proteins and peptides. The UNRES (UNited RESidue) coarse-grained force field allows treating disulfide bonds in two ways: as static (formed or broken in the simulation) or dynamic (all specified cysteine residues can form and break disulfide bonds during simulation). The comparison between those two approaches of disulfide-bond treatment is presented for protein folding on the example of four small β - and α + β proteins with one, two, three and four disulfide bonds. The results clearly show that proper disulfide bond treatment is important in simulations and significantly enhances the quality of folded structures.

6

Coarse-grained modeling of protein structure, dynamics and protein-protein interactions

Koliński A., Kmiecik S., Jamróz M., Błaszczyk M., Kouza M., Kurciński M.

TASK Quarterly : scientific bulletin of Academic Computer Centre in Gdansk

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2014

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Vol. 18, No 3

219--229

EN

Theoretical prediction of protein structures and dynamics is essent ial for understanding the molecular basis of drug action, metabolic and signaling pathway s in living cells, designing new technologies in the life science and material sciences . We developed and validated a novel multiscale methodology for the study of protein folding proces ses including flexible docking of proteins and peptides. The new modeling technique starts fr om coarse-grained large-scale simulations, followed by selection of the most plausible final structu res and intermediates and, finally, by an all-atom rectification of the obtained structures. Except f or the most basic bioinformatics tools, the entire computational methodology is based on the models an d algorithms developed in our lab. The coarse-grained simulations are based on a high-resol ution lattice representation of protein structures, a knowledge based statistical for ce field and efficient Monte Carlo dynamics schemes, including Replica Exchange algorithms. This p aper focuses on the description of the coarse-grained CABS model and its selected applications.

7

Fast closure of long loops at the initiation of the folding transition of globular proteins studied by time-resolved FRET-based methods

Orevi T., Rahamim G., Shemesh S., Ben Ishay E., Amir D., Haas E.

Bio-Algorithms and Med-Systems

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2014

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Vol. 10, no. 4

169--193

EN

The protein folding problem would be considered “solved” when it will be possible to “read genes”, i.e., to predict the native fold of proteins, their dynamics, and the mechanism of fast folding based solely on sequence data. The long-term goal should be the creation of an algorithm that would simulate the stepwise mechanism of folding, which constrains the conformational space and in which random search for stable interactions is possible. Here, we focus attention on the initial phases of the folding transition starting with the compact disordered collapsed ensemble, in search of the initial sub-domain structural biases that direct the otherwise stochastic dynamics of the backbone. Our studies are designed to test the “loop hypothesis”, which suggests that fast closure of long loop structures by non-local interactions between clusters of mainly non-polar residues is an essential conformational step at the initiation of the folding transition of globular proteins. We developed and applied experimental methods based on time-resolved resonance excitation energy transfer (trFRET) measurements combined with fast mixing methods and studied the initial phases of the folding of Escherichia coli adenylate kinase (AK). A series of AK mutants were prepared, in which the ends of selected backbone segments that form long closed loops or secondary structure elements were labeled by donors and acceptors of excitation energy. The end-to-end distance distributions of such segments were determined under equilibrium and during the fast folding transitions. These experiments show that three out of seven long loops that were labeled in the AK molecule are closed very early in the transition. The N terminal 26-residue loop (loop I) is closed in <200 μs after the initiation of folding, while the β strand included in loop I is still disordered. The closure of the second 44-residue loop (loop II, which starts at the end of loop I) is also complete within <300 μs. Four other loops as well as five secondary structures of the CORE domain of AK (an α helix and four β strands) are formed at a late step, at a rate of 0.5±0.3 s–1, the rate of the cooperative folding of the molecule. These experiments reveal a hierarchically ordered pathway of folding of the AK molecule, ranging from microseconds to seconds. The results reviewed here, obtained mainly from studying a small number of model proteins, support the counterintuitive mechanism whereby non-local interactions are effective in the initiation of the folding pathways. The experiments presented demonstrate the importance of mapping the rates of sub-domain structural transitions along the folding transition, in situ, in the context of the other sections of the chain, whether folded or disordered. These experiments also show the power of the time-resolved FRET measurements in achieving this goal. A large body of data obtained by theoretical and experimental studies that support, or can accommodate, the loop hypothesis is reviewed. We suggest that mapping multiple sub-domain structural transitions during the refolding transition of many proteins using the approach presented here will refine the conclusions and help reveal some common principles of the initiation of the folding. To achieve this goal, the trFRET measurements should be combined with mutagenesis experiments where the role of selected residue clusters will be tested by perturbation mutations. Nevertheless, the solution of the protein folding problem depends on the application of many additional approaches, both experimental and theoretical, while the approach presented here is only a small section of the big puzzle.

8

A kinetic mechanism for in vivo protein folding

Cruzeiro L.

Bio-Algorithms and Med-Systems

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2014

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Vol. 10, no. 3

117--127

EN

For many decades now, the solution to the protein folding problem has been sought within the thermodynamic hypothesis of Anfinsen. Instead, the work discussed here is concerned with protein folding in vivo and assumes that the solution lies within a generalization of the kinetic, nonequilibrium mechanism first proposed by Levinthal. Accordingly, two different initial conditions, namely, a fully extended and a helical chain, are tested and pathways to the native state are generated via targeted molecular dynamics. The energetic and structural analysis indicates that a helical initial condition is to be preferred over an extended one. These results are set against the broader context of in vitro protein refolding experiments and theories and are found to be in agreement with the recent experimental observations about the influence of the ribosome on the structure of, and on the folding from, nascent chains.

9

Dwie twarze struktury przestrzennej białek – zastosowanie wiedzy o białkach samoistnie nieuporządkowanych w racjonalnym projektowaniu leków

Górka A., Bonarek P.

Studia i Materiały Informatyki Stosowanej

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2013

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nr 10

7--12

PL

Białka są podstawowymi składnikami żywych komórek. Prawidłowe rozumienie cech ich struktury przestrzennej jest kluczowe dla zrozumienia ich funkcjonowania w organizmach żywych. Białka mogą przebywać w czterech wyróżnionych stanach organizacji struktury przestrzennej: uporządkowanym, stopionej globuli, pre-stopionej globuli i kłębka statystycznego. Funkcje białek mogą być związane z każdym tych stanów, a co ważniejsze, z przejściami pomiędzy tymi stanami. Znacząca liczba białek w przyrodzie zbudowana jest z mieszaniny rejonów uporządkowanych oraz samoistnie nieuporządkowanych, które pełnią ważne role w procesach przekazu sygnału, regulacji cyklu komórkowego i wielu innych. Standardowe podejście do racjonalnego projektowania leków nie sprawdza się w przypadku białek samoistnie nieuporządkowanych (IDPs) i wymaga zmodyfikowanej strategii postępowania. Jednym z atrakcyjnych celów terapeutycznych dla przemysłu farmaceutycznego są krótkie fragmenty łańcucha aminokwasowego pełniące funkcje elementów rozpoznawania molekularnego (MoRFs), które porządkują swoją strukturę w różnorodnych i licznych oddziaływaniach z innymi białkami. Charakterystyczną cechą MoRFs-ów jest ich częste występowanie w rejonach samoistnie nieuporządkowanych łańcucha polipeptydowego.

EN

Proteins are an essential component of living cells. Proper understanding of the properties of their structure is crucial to understanding their function in nature. The proteins and their fragments may exist in four states of structure organization: ordered, molten globule, pre molten globule and random coil. The particular function of proteins depend on any one of these states or a transition between them. A significant proportion of proteins in nature is composed of a mixture of ordered and intrinsically disordered regions, that fulfil important roles in the processes like signal transduction, cell cycle regulation and many others. The standard approach for rational drug design does not work for intrinsically disordered proteins (IDPs) and requires modified strategies. Furthermore, the majority of proteins with long intrinsically disordered regions (IDRs) use short molecular recognition elements (MoRFs), which undergo transition from disorder to order state and adopt various structures in numerous protein protein interactions. These interactions are an attractive therapeutic target for the pharmaceutical industry in the process of rational drug design.

10

The identification and the elimination of clashes in the structure of an early-stage intermediate in the protein folding process

Baster Z.

Bio-Algorithms and Med-Systems

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2013

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Vol. 9, no. 4

199--207

EN

The model (under consideration) to simulate the protein folding process assumes two steps: early stage (ES) and late stage (LS). The first is assumed to define the preliminary structure, which when applied to an optimization procedure, may produce the proper structure of the protein. However, the ES model produces the structures with clashes. This work demonstrates the possible solution to remove clashes before proceeding to the LS. Additionally, the presented solution describes mathematically the precession phenomenon, which might be useful in other fields of studies aside from protein folding such as medical imaging, quantum physics, and astronomy.

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Theoretical approach to the common events in every living cell – protein folding and protein misfolding

Vaibhav V. K., Sachin S. L.

International Letters of Chemistry, Physics and Astronomy

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2012

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Vol. 3

41-51

EN

Folding and unfolding are crucial ways of regulating biological activity and targeting proteins to different cellular locations. Aggregation of misfolded proteins that escape the cellular quality-control mechanisms is a common feature of a wide range of highly debilitating and increasingly prevalent diseases. Protein misfolding is a common event in living cells. Molecular chaperones not only assist protein folding; they also facilitate the degradation of misfolded polypeptides. Protein folding is governed solely by the protein itself, scientists discovered that some proteins have helped in the process called chaperones. When the intracellular degradative capacity is exceeded, juxtanuclear aggresomes are formed to sequester misfolded proteins. Misfolding of newly formed proteins not only results in a loss of physiological function of the protein but also may lead to the intra- or extra- cellular accumulation of that protein. A number of diseases have been shown to be characterised by the accumulation of misfolded proteins, notable example being Alzheimer's disease.

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O kilku osobliwościach w oddziaływaniach molekuł

Piela L.

Wiadomości Chemiczne

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2011

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[Z] 65, 11-12

935-952

EN

The ground state electronic energy represents a complicated function of the nuclear coordinates. Even for relatively small molecules this function may have many minima in the corresponding "energy landscape", very often myriads of minima, each of them corresponding to a stable configuration of the nuclei. This is why predicting the lowest-energy conformation or configuration represents a formidable task. There were many attempts to solve this problem for protein molecules, for which it is believed their native conformation corresponds to the lowest free energy. The challenge to find this conformation from a given sequence of amino acids is known as a "second genetic code". In fact all of these attempts based on some smoothing of the energy landscape. In the article some of these smoothing techniques are described, from a generic one to those, which finally turned out to be highly successful in finding native structures of globular proteins. When discussing the contributions to the conformational energy the importance of the hydrophobic effect as well as of the electrostatic interactions has been stressed. In particular it turned out that the dipole moments of the NH and of the CO bonds in proteins functioning in nature are oriented to good accuracy along the local intramolecular electric field. Thanks to enormous effort of the protein folding community it is possible to design such amino acid sequences, which fold to the desired protein 3D structure. A certain reliable theoretical technique of protein folding has been used to study a possibility of conformational autocatalysis. It turned out that a small protein of 32 amino acids, with carefully predesigned amino acid sequence, exhibits indeed such an effect, which may be seen as a model of the prion disease propagation.

13

Configuration and Conformation in the Informatic Molecular Technology

Znamirowski L.

Theoretical and Applied Informatics

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2006

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Vol. 18, nr 1

15-28

EN

Processes of sequential forcing of the nanostructure configuration, and also the self-replication and self-organization processes which may be performed in the nanoprocess arę the phenomena that may make successful the direct materials nano-fabrication in the systems of informatics, possible. Since the nanostructures are being created from the basie elements represented by molecules, the arising structure is adopting a certain spatial shape. The spatial forming of the nanostructures has an essential meaning from a point of view of the created types of desirable products and their properties both as a finał molecular technology result and as functioning nanostructures in signal transduction pathways inside the running nanoprocess. In the paper the problem of determining of the nanostructures conformation is discussed in case of free conformation forming as well as in case of constraints existence.

14

Elements of non-random structure in the unfolded states of proteins : location and possible implications for protein folding mechanisms

Nikiforovicz G. V.

Polimery

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2003

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T. 48, nr 1

44-49

EN

This study introduces a simple computational procedure to search protein sequences for the segments with above average propensity to adopt non-random structures (which includes the native-like structure) in the unfolded state. The procedure consists of systematical conformational analysis of all overlapping hexapeptide segments in the protein sequence. The main aim of the computational approach is to determine the 3D structure most preferable for a given residue in the protein sequence, as determined by local interactions within the set of hexapeptides featuring the particular residue under consideration. Specifically, this study focuses on four types of "template" 3D structures that may be adopted by a hexapeptide, namely beta-strand, alpha-helix, beta-turn and the native-like structure of the folded state (assumed to be known). The study discusses also the possible importance of such segments for the different molecular mechanism of folding of the two prototypical proteins, namely the 65-residue barley chymotrypsin inhibitor 2 (CI2) and the 110-residue ribonuclease from Bacillus anzyloliquefaciens (barnase). The computational results suggest that dynamic equilibrium in the unfolded state for the continuous fragment 6-27 in CI2 will likely prefer the native-like structure that may be preserved during folding. For barnase, oil the contrary, dynamic equilibrium preferring the native-like structure most likely will occur in the unfolded state only at several small separate fragments, so the large non-native non-random segments of the unfolded state have to be restructured during folding.

PL

Opracowano prostą procedurę obliczeniową do badania sekwencji białek w odniesieniu do segmentów o większej niż średnia skłonności do przybierania postaci struktur uporządkowanych (które zawierają struktury takie same jak macierzyste) w stanie rozwiniętym. Procedura obejmuje systematyczną analizę konformacyjną wszystkich nachodzących na siebie segmentów heksapeptydowych w sekwencji białka. Głównym celem tego przybliżenia obliczeniowego jest określenie najbardziej uprzywilejowanej w przypadku danych reszt aminokwasowych w sekwencji białkowej struktury 3D, zgodnej z wynikami uzyskanymi na podstawie oceny lokalnych oddziaływań w układzie heksapeptydów obrazujących rozważane tu reszty aminokwasów. Skupiono się zwłaszcza na (przyjętych jako znane) czterech typach matrycowych struktur 3D, które mogą być przybierane przez heksapeptydy, mianowicie na strukturze P (fi-strand), a-helisy (a-helix), P-zgiętej ($-turn) oraz na strukturze takiej jak macierzysta w stanie rozwiniętym. Przedyskutowano także możliwy udział takich segmentów w różnych molekularnych mechanizmach zwijania dwu prototypowych białek: złożonego z 65 reszt aminokwasowych inhibitora 2-chymotrypsyny jęczmienia (C12) oraz 110-aminokwasowej rybonukleazy z Bacillus amyloliąuefaciens (barnazy). Wyniki obliczeń wskazują, że równowaga dynamiczna w stanie rozwiniętym ciągłego fragmentu 6-27 w C12 powinna preferować struktury takie jak macierzyste, które mogą zostać zachowane podczas zwijania (rys. 1 i 3). Przeciwnie, w przypadku barnazy równowaga dynamiczna uprzywilejowująca struktury podobne macierzystym najczęściej występuje w stanie rozwiniętym tylko w nielicznych małych wydzielonych fragmentach, zatem duże niemacierzys-te uporządkowane segmenty w tym stanie muszą być odtworzone podczas zwijania.

15

Structure of Proteins : New Approach to Molecular Modeling

Koliński A., Rotkiewicz P., Skolnick J.

Polish Journal of Chemistry

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2001

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Vol. 75, nr 4

587-599

EN

The force field and Monte Carlo sampling method of our recently developed reduced model of proteins is described. Recent applications of the models include ab initio structure prediction for small globular proteins, modeling of protein structure based on distantly homologous (or analogous) structural templates, assembly of protein structure from sparse experimental data, and computational studies of protein folding dynamics and thermodynamics. The newest application, described in this paper, enables the prediction of low-to-moderate resolution coordinates of the parts of protein structure that are missed in incomplete PDB files.

16

Ab initio protein foldings - is conformational space searching enough?

Olszewski K.A.

Polish Journal of Chemistry

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1998

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Vol. 72, nr 7S

1667-1679

EN

Ab initio protein folding is a common name for protein structure prediction approaches, that explore the conformational space of a protein using a model of a protein and a simple, carefully designed, potential energy function. Attempts to predict the native state of the protein or to reproduce the folding pathway from a set of simple rules are essential for an understanding of the physico-chemical rules that govern the folding process. Noteworthy, a number of new techniques for protein structure/function prediction that widen the search space and the meaning of the potential energy function have emerged. In this paper the variety of approaches to protein structure or function prediction are discussed and classified with respect to their distribution in the general protein sequence-structure space.