Protein intrachain contact prediction with most interacting residues (MIR)

AbstractThe transition state ensemble during the folding process of globular proteins occurs when a sufficient number of intrachain contacts are formed, mainly, but not exclusively, due to hydrophobic interactions. These contacts are related to the folding nucleus, and they contribute to the stability of the native structure, although they may disappear after the energetic barrier of transition states has been passed. A number of structure and sequence analyses, as well as protein engineering studies, have shown that the signature of the folding nucleus is surprisingly present in the native three-dimensional structure, in the form of closed loops, and also in the early folding events. These findings support the idea that the residues of the folding nucleus become buried in the very first folding events, therefore helping the formation of closed loops that act as anchor structures, speed up the process, and overcome the Levinthal paradox. We present here a review of an algorithm intended to simulate in a discrete space the early steps of the folding process. It is based on a Monte Carlo simulation where perturbations, or moves, are randomly applied to residues within a sequence. In contrast with many technically similar approaches, this model does not intend to fold the protein but to calculate the number of non-covalent neighbors of each residue, during the early steps of the folding process. Amino acids along the sequence are categorized as most interacting residues (MIRs) or least interacting residues. The MIR method can be applied under a variety of circumstances. In the cases tested thus far, MIR has successfully identified the exact residue whose mutation causes a switch in conformation. This follows with the idea that MIR identifies residues that are important in the folding process. Most MIR positions correspond to hydrophobic residues; correspondingly, MIRs have zero or very low accessible surface area. Alongside the review of the MIR method, we present a new postprocessing method called smoothed MIR (SMIR), which refines the original MIR method by exploiting the knowledge of residue hydrophobicity. We review known results and present new ones, focusing on the ability of MIR to predict structural changes, secondary structure, and the improved precision with the SMIR method.

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Functional and Early Folding Residues are separated in proteins to increase evolvability and robustness

10.1101/290627 ◽

2018 ◽

Cited By ~ 1

Author(s):

Sebastian Bittrich ◽

Michael Schroeder ◽

Dirk Labudde

Keyword(s):

Protein Folding ◽

Hydrophobic Interactions ◽

Three Dimensional ◽

Accessible Surface Area ◽

Topological Descriptors ◽

Dimensional Structure ◽

Folding Process ◽

Three Dimensional Structure ◽

Starting Point ◽

Local Conformations

AbstractThe three-dimensional structure of proteins captures evolutionary ancestry, and serves as starting point to understand the origin of diseases. Proteins adopt their structure autonomously by the process of protein folding. Over the last decades, the folding process of several proteins has been studied with temporal and spatial resolution which allowed the identification of so-called Early Folding Residues (EFR) in the folding process. These structurally relevant residues become affected early in the folding process and initiate the formation of secondary structure elements and guide their assembly.Using a dataset of 30 proteins and 3,337 residues provided by the Start2Fold database, discriminative features of EFR were identified by a systematical characterization. Therefore, proteins were represented as graphs in order to analyze topological descriptors of EFR. They constitute crucial connectors of protein regions which are distant at sequence level. Especially, these residues exhibit a high number of non-covalent contacts such as hydrogen bonds and hydrophobic interactions. This tendency also manifest as energetically stable local regions in a knowledge-based potential. Conclusively, these features are not only characteristic for EFR but also differ significantly with respect to functional residues. This unveils a split between structurally and functionally relevant residues in proteins which can drastically improve their evolvability and robustness.The characteristics of EFR cannot be attributed to trivial features such as the accessible surface area. Thus, the presented features are novel descriptors for EFR of the folding process. Potentially, these features can be used to design classifiers to predict EFR from structure or to implement structure quality assessment programs. The shown division of labor between functional and EFR has implications for the prediction of mutation effects as well as protein design and can provide insights into the evolution of proteins. Finally, EFR allow to further the understanding of the protein folding process due to their pivotal role.Author summaryProteins are chains of amino acids which adopt a three-dimensional structure and are then able to catalyze chemical reactions or propagate signals in organisms. Without external influence, most proteins fold into their correct structure, and a small number of Early Folding Residues (EFR) have been shown to become affected at the very start of the process. We demonstrated that these residues are located in energetically stable local conformations. EFR are in contact to many other residues of a protein and act as hubs between sequentially distant regions of a proteins. These distinct characteristics can give insights into what causes certain residues to initiate and guide the folding process. Furthermore, it can help our understanding regarding diseases such as Alzheimer’s or amyotrophic lateral sclerosis which are the result of protein folding gone wrong. We further found that the structurally relevant EFR are almost exclusively non-functional. Proteins separate structure and function, which increases evolvability and robustness and gives guidance for the artificial design of proteins.

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Heat and SDS insensitive NDK dimers are largely stabilised by hydrophobic interaction to form functional hexamer in Mycobacterium smegmatis.

Acta Biochimica Polonica ◽

10.18388/abp.2013_1972 ◽

2013 ◽

Vol 60 (2) ◽

Cited By ~ 3

Author(s):

Muthu Arumugam ◽

Parthasarathi Ajitkumar

Keyword(s):

Hydrophobic Interaction ◽

Hydrophobic Interactions ◽

Three Dimensional ◽

Nucleoside Diphosphate Kinase ◽

Dimensional Structure ◽

Recombinant Enzymes ◽

Basic Subunit ◽

Oligomeric Form ◽

The Stability ◽

And Function

The primary structure and function of nucleoside diphosphate kinase (NDK), a substrate non-specific enzyme involved in the maintenance of nucleotide pools is also implicated to play pivotal roles in many other cellular processes. NDK is conserved from bacteria to human and forms a homotetramer or hexamer to exhibit its biological activity. However, the nature of the functional oligomeric form of the enzyme differs among different organisms. The functional form of NDKs from many bacterial systems, including that of the human pathogen, Mycobacterium tuberculosis (MtuNDK), is a hexamer, although some bacterial NDKs are tetrameric in nature. The present study addresses the oligomeric property of MsmNDK and how a dimer, the basic subunit of a functional hexamer, is stabilized by hydrogen bonds and hydrophobic interactions. Homology modeling was generated using the three-dimensional structure of MtuNDK as a template; the residues interacting at the monomer-monomer interface of MsmNDK were mapped. Using recombinant enzymes of wild type, catalytically inactive mutant, and monomer-monomer interactive mutants of MsmNDK, the stability of the dimer was verified under heat, SDS, low pH, and methanol. The predicted residues (Gln17, Ser24 and Glu27) were engaged in dimer formation, however the mutated proteins retained the ATPase and GTPase activity even after introducing single (MsmNDK- Q17A, MsmNDK-E27A, and MsmNDK-E27Q) and double (MsmNDK-E27A/Q17A) mutation. However, the monomer-monomer interaction could be abolished using methanol, indicating the stabilization of the monomer-monomer interaction by hydrophobic interaction.

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PUTRACER: A NOVEL METHOD FOR IDENTIFICATION OF CONTINUOUS-DOMAINS IN MULTI-DOMAIN PROTEINS

Journal of Bioinformatics and Computational Biology ◽

10.1142/s021972001340012x ◽

2013 ◽

Vol 11 (01) ◽

pp. 1340012 ◽

Cited By ~ 1

Author(s):

SEYED SHAHRIAR ARAB ◽

MOHAMMADBAGHER PARSA GHARAMALEKI ◽

ZAIDDODINE PASHANDI ◽

REZVAN MOBASSERI

Keyword(s):

Protein Structures ◽

Three Dimensional ◽

Accessible Surface Area ◽

Computer Assisted ◽

Correct Assignment ◽

Critical Boundary ◽

Novel Method ◽

Accessible Surface ◽

A Chain

Computer assisted assignment of protein domains is considered as an important issue in structural bioinformatics. The exponential increase in the number of known three dimensional protein structures and the significant role of proteins in biology, medicine and pharmacology illustrate the necessity of a reliable method to automatically detect structural domains as protein units. For this aim, we have developed a program based on the accessible surface area (ASA) and the hydrogen bonds energy in protein backbone (HBE). PUTracer (Protein Unit Tracer) is built on the features of a fast top-down approach to cut a chain into its domains (contiguous domains) with minimal change in ASA as well as HBE. Performance of the program was assessed by a comprehensive benchmark dataset of 124 protein chains, which is based on agreement among experts (e.g. CATH, SCOP) and was expanded to include structures with different types of domain combinations. Equal number of domains and at least 90% agreement in critical boundary accuracy were considered as correct assignment conditions. PUTracer assigned domains correctly in 81.45% of protein chains. Although low critical boundary accuracy in 18.55% of protein chains leads to the incorrect assignments, adjusting the scales causes to improve the performance up to 89.5%. We discuss here the success or failure of adjusting the scales with provided evidences. Availability: PUTracer is available at http://bioinf.modares.ac.ir/software/PUTracer/

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Role of LHCII-containing macrodomains in the structure, function and dynamics of grana

Functional Plant Biology ◽

10.1071/pp99069_co ◽

2000 ◽

Vol 27 (3) ◽

pp. 279 ◽

Cited By ~ 2

Author(s):

G. Garab ◽

L. Mustárdy

Keyword(s):

Excitation Energy ◽

Long Range ◽

Structural Changes ◽

Higher Plants ◽

Three Dimensional ◽

Dimensional Structure ◽

Lateral Heterogeneity ◽

Long Distance ◽

3D Network

In higher plants and green algae two types of thylakoids are distinguished, granum (stacked) and stroma (unstacked) thylakoids. They form a three-dimensional (3D) network with large lateral heterogeneity: photosystem II (PSII) and the associated main chlorophyll a/b light-harvesting complex (LHCII) are found predominantly in the stacked region, while PSI and LHCI are located mainly in the unstacked region of the membrane. This picture emerged from the discovery of the physical separation of the two photosystems (Boardman and Anderson 1964). Granal chloroplasts possess significant flexibility, which is essential for optimizing the photosynthetic machinery under various environmental conditions. However, our understanding concerning the assembly, structural dynamics and regulatory functions of grana is far from being complete. In this paper we overview the significance of the three-dimensional structure of grana in the absorption properties, ionic equilibrations, and in the diffusion of membrane components between the stacked and unstacked regions. Further, we discuss the role of chiral macrodomains in the grana. Lateral heterogeneity of thylakoid membranes is proposed to be a consequence of the formation of macrodomains constituted of LHCII and PSII; their long range order permits long distance migration of excitation energy, which explains the energetic connectivity of PSII particles. The ability of macrodomains to undergo light-induced reversible structural changes lends structural flexibility to the granum. In purified LHCII, which has also been shown to form stacked lamellar aggregates with long range chiral order, excitation energy migrates for large distances; these macroaggregates are also capable of undergoing light-induced reversible structural changes and fluorescence quenching. Hence, some basic properties of grana appear to originate from its main constituent, the LHCII.

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Evidence for a Conformational Change in Actin Induced by Fimbrin (N375) Binding

The Journal of Cell Biology ◽

10.1083/jcb.139.2.387 ◽

1997 ◽

Vol 139 (2) ◽

pp. 387-396 ◽

Cited By ~ 81

Author(s):

Dorit Hanein ◽

Paul Matsudaira ◽

David J. DeRosier

Keyword(s):

Actin Filaments ◽

Structural Changes ◽

Three Dimensional ◽

Binding Domain ◽

Actin Binding ◽

Dimensional Structure ◽

Binding Surface ◽

Actin Binding Domain ◽

Actin Structure ◽

Signal Transduction Proteins

Fimbrin belongs to a superfamily of actin cross-linking proteins that share a conserved 27-kD actin-binding domain. This domain contains a tandem duplication of a sequence that is homologous to calponin. Calponin homology (CH) domains not only cross-link actin filaments into bundles and networks, but they also bind intermediate filaments and some signal transduction proteins to the actin cytoskeleton. This fundamental role of CH domains as a widely used actin-binding domain underlines the necessity to understand their structural interaction with actin. Using electron cryomicroscopy, we have determined the three-dimensional structure of F-actin and F-actin decorated with the NH2-terminal CH domains of fimbrin (N375). In a difference map between actin filaments and N375-decorated actin, one end of N375 is bound to a concave surface formed between actin subdomains 1 and 2 on two neighboring actin monomers. In addition, a fit of the atomic model for the actin filament to the maps reveals the actin residues that line, the binding surface. The binding of N375 changes actin, which we interpret as a movement of subdomain 1 away from the bound N375. This change in actin structure may affect its affinity for other actin-binding proteins and may be part of the regulation of the cytoskeleton itself. Difference maps between actin and actin decorated with other proteins provides a way to look for novel structural changes in actin.

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Structure of Human Apolactoferrin at 2.0 Å Resolution. Refinement and Analysis of Ligand-Induced Conformational Change

Acta Crystallographica Section D Biological Crystallography ◽

10.1107/s0907444998004417 ◽

1998 ◽

Vol 54 (6) ◽

pp. 1319-1335 ◽

Cited By ~ 46

Author(s):

Geoffrey B. Jameson ◽

Bryan F. Anderson ◽

Gillian E. Norris ◽

David H. Thomas ◽

Edward N. Baker

Keyword(s):

Surface Area ◽

Conformational Change ◽

Crystal Packing ◽

Three Dimensional ◽

Chloride Ions ◽

Dimensional Structure ◽

Iron Binding ◽

Data Set ◽

Binding Cleft ◽

Accessible Surface

The three-dimensional structure of a form of human apolactoferrin, in which one lobe (the N-lobe) has an open conformation and the other lobe (the C-lobe) is closed, has been refined at 2.0 Å resolution. The refinement, by restrained least-squares methods, used synchrotron radiation X-ray diffraction data combined with a lower resolution diffractometer data set. The final refined model (5346 protein atoms from residues 1–691, two Cl− ions and 363 water molecules) gives a crystallographic R factor of 0.201 (R free = 0.286) for all 51305 reflections in the resolution range 10.0–2.0 Å. The conformational change in the N-lobe, which opens up the binding cleft, involves a 54° rotation of the N2 domain relative to the N1 domain. This also results in a small reorientation of the two lobes relative to one another with a further ∼730 Å2 of surface area being buried as the N2 domain contacts the C-lobe and the inter-lobe helix. These new contacts also involve the C-terminal helix and provide a mechanism through which the conformational and iron-binding status of the N-lobe can be signalled to the C-lobe. Surface-area calculations indicate a fine balance between open and closed forms of lactoferrin, which both have essentially the same solvent-accessible surface. Chloride ions are bound in the anion-binding sites of both lobes, emphasizing the functional significance of these sites. The closed configuration of the C-lobe, attributed in part to weak stabilization by crystal packing interactions, has important implications for lactoferrin dynamics. It shows that a stable closed structure, essentially identical to that of the iron-bound form, can be formed in the absence of iron binding.

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Computing the stability diagram of the Trp-cage miniprotein

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0804775105 ◽

2008 ◽

Vol 105 (46) ◽

pp. 17754-17759 ◽

Cited By ~ 119

Author(s):

Dietmar Paschek ◽

Sascha Hempel ◽

Angel E. García

Keyword(s):

Energy Difference ◽

Accessible Surface Area ◽

Stability Diagram ◽

Solvent Accessible Surface Area ◽

Denatured State ◽

Elevated Pressures ◽

Explicit Solvent ◽

Accessible Surface ◽

The Stability ◽

Dynamics Simulations

We report molecular dynamics simulations of the equilibrium folding/unfolding thermodynamics of an all-atom model of the Trp-cage miniprotein in explicit solvent. Simulations are used to sample the folding/unfolding free energy difference and its derivatives along 2 isochores. We model the ΔGu(P,T) landscape using the simulation data and propose a stablility diagram model for Trp-cage. We find the proposed diagram to exhibit features similar to globular proteins with increasing hydrostatic pressure destabilizing the native fold. The observed energy differences ΔEu are roughly linearly temperature-dependent and approach ΔEu = 0 with decreasing temperature, suggesting that the system approached the region of cold denaturation. In the low-temperature denatured state, the native helical secondary structure elements are largely preserved, whereas the protein conformation changes to an “open-clamp” configuration. A tighter packing of water around nonpolar sites, accompanied by an increasing solvent-accessible surface area of the unfolded ensemble, seems to stabilize the unfolded state at elevated pressures.

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Anchoring Carboxyl Functionalized Gold-Aryl Nanoparticles to Graphene Oxide Platforms for Environmental Nanoremediation

10.26434/chemrxiv.13210802 ◽

2020 ◽

Author(s):

Javad Parambath ◽

Najrul Hussain ◽

Mahreen Arooj ◽

Maria Omastova ◽

Mohamed Chehimi ◽

...

Keyword(s):

Graphene Oxide ◽

Surface Area ◽

Hydrophobic Interactions ◽

Catalytic Reduction ◽

Accessible Surface Area ◽

Total Surface Area ◽

Solvent Accessible Surface Area ◽

Sodium Borohydride Reduction ◽

Current Densities ◽

Accessible Surface

Graphene oxide (GO) was decorated with gold-aryl (Au-C) nanoparticles AuNPs-COOH by sodium borohydride reduction of aryldiazonium tetrachloroaurate(III) salt at room temperature in aqueous solutions. BET (Brunauer-Emmett-Teller) measurements supported the anchoring of GO by AuNPs modified with carboxyl functional groups; surface area dropped significantly. Morphology of AuNPs-COOH/GO nanocomposite (NC) was probed using AFM and TEM and images showed surface roughness and wrinkling. Molecular dynamics (MD) calculations endowed support of favorable wrinkling at the edges and carboxyl intercalation to GO surface of types p-p, hydrogen bonding, and hydrophobic interactions. Solvent accessible surface area calculations (SASA) of GO showed a decrease in total surface area, in agreement with BET results. Environmental nanoremediation of the catalytic reduction of nitrophenol and the electrocatalytic reduction of CO2 (model pollutants) were investigated. The apparent rate constants Kapp of the four catalytic reduction cycles of nitrophenol were measured. The highest value is 1.17 × 10-1 min-1 for the first cycle which decreased to 4.49 × 10-2 min-1 for the fourth cycle. Electrocatalytic studies revealed that the NC enhanced the CO2 reduction. The NC exhibited higher current densities in the CO2 solution saturated (48 mA/cm2) compared to N2 (37 mA/cm2), indicating its superior catalytic activity in CO2 reduction.

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