Researcher:
Sayar, Mehmet

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Mehmet

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Sayar

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Researcher Of Publications: search.filters.isAuthorOfPublication.2a94231a-b229-4005-9e55-042142660859

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    Representation of the conformational ensemble of peptides in coarse grained simulations
    (American Institute of Physics (AIP) Publishing, 2020) N/A; N/A; Department of Mechanical Engineering; Özgür, Beytullah; Sayar, Mehmet; PHD Student; Faculty Member; Department of Mechanical Engineering; Graduate School of Sciences and Engineering; College of Engineering; N/A; N/A; 109820
    In their native state, many proteins/peptides display an ensemble of conformations, rather than a unique tertiary structure. Novel experimental techniques have enabled a quantitative analysis of this structural heterogeneity. In molecular dynamics simulations, however, capturing this conformational ensemble quantitatively remains a major challenge even with all atom simulations. In coarse grained (CG) simulations, with fewer degrees of freedom, representation of the conformational ensemble becomes more problematic. Here, we revisit a CG model from our group, which was designed to address the conformational transferability problem by using the LK alpha 14 peptide as a model system. The LK alpha 14 peptide transitions from a random/unstructured state in dilute solution to a solely alpha -helical conformation upon aggregation as evidenced by circular dichroism. Here, we demonstrate that the structure/physics based approach, used in the original parameterization of our CG model, strongly depends on the reference system chosen and excluded volume interactions that are often considered to be of secondary importance. We first tune the excluded volume parameters by using both alpha -helix and beta -sheet type structures as reference and then update the nonbonded interactions by using a goodness-of-fit metric for representation of the conformational ensemble of LK alpha 14. We demonstrate that the updated model can recover the whole conformational ensemble quantitatively while maintaining the aggregation driven conformational transition. This balanced parametrization with regard to alternative secondary structures opens the door for the generalization of the CG model to other sequences, which we demonstrate on a beta -sheet forming triblock peptide.
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    The introduction of hydrogen bond and hydrophobicity effects into the rotational isomeric states model for conformational analysis of unfolded peptides
    (Iop Publishing Ltd, 2009) N/A; Department of Mechanical Engineering; Department of Chemical and Biological Engineering; Engin, Özge; Sayar, Mehmet; Erman, Burak; Master Student; Faculty Member; Faculty Member; Department of Mechanical Engineering; Department of Chemical and Biological Engineering; Graduate School of Sciences and Engineering, College of Engineering; College of Engineering; N/A; 109820; 179997
    Relative contributions of local and non-local interactions to the unfolded conformations of peptides are examined by using the rotational isomeric states model which is a Markov model based on pairwise interactions of torsion angles. the isomeric states of a residue are well described by the Ramachandran map of backbone torsion angles. the statistical weight matrices for the states are determined by molecular dynamics simulations applied to monopeptides and dipeptides. Conformational properties of tripeptides formed from combinations of alanine, valine, tyrosine and tryptophan are investigated based on the Markov model. Comparison with molecular dynamics simulation results on these tripeptides identifies the sequence-distant long-range interactions that are missing in the Markov model. these are essentially the hydrogen bond and hydrophobic interactions that are obtained between the first and the third residue of a tripeptide. a systematic correction is proposed for incorporating these long-range interactions into the rotational isomeric states model. Preliminary results suggest that the Markov assumption can be improved significantly by renormalizing the statistical weight matrices to include the effects of the long-range correlations.
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    Conformation and aggregation of peptides at interfaces
    (Cell Press, 2014) Department of Mechanical Engineering; Sayar, Mehmet; Faculty Member; Department of Mechanical Engineering; College of Engineering; 109820
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    Modeling adsorption, conformation, and orientation of the Fis1 tail anchor at the mitochondrial outer membrane
    (MDPI, 2022) Dunn, Cory D.; N/A; Department of Mechanical Engineering; Özgür, Beytullah; Sayar, Mehmet; PhD Student; Faculty Member; Department of Mechanical Engineering; Graduate School of Sciences and Engineering; College of Engineering; N/A; 109820
    Proteins can be targeted to organellar membranes by using a tail anchor (TA), a stretch of hydrophobic amino acids found at the polypeptide carboxyl-terminus. The Fis1 protein (Fis1p), which promotes mitochondrial and peroxisomal division in the yeast Saccharomyces cerevisiae, is targeted to those organelles by its TA. Substantial evidence suggests that Fis1p insertion into the mitochondrial outer membrane can occur without the need for a translocation machinery. However, recent findings raise the possibility that Fis1p insertion into mitochondria might be promoted by a proteinaceous complex. Here, we have performed atomistic and coarse-grained molecular dynamics simulations to analyze the adsorption, conformation, and orientation of the Fis1(TA). Our results support stable insertion at the mitochondrial outer membrane in a monotopic, rather than a bitopic (transmembrane), configuration. Once inserted in the monotopic orientation, unassisted transition to the bitopic orientation is expected to be blocked by the highly charged nature of the TA carboxyl-terminus and by the Fis1p cytosolic domain. Our results are consistent with a model in which Fis1p does not require a translocation machinery for insertion at mitochondria.
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    From macroscopic to molecular interfaces: how do they alter protein conformation?
    (Cell Press, 2015) Department of Mechanical Engineering; N/A; Sayar, Mehmet; Dalgıçdır, Cahit; Faculty Member; PhD Student; Department of Mechanical Engineering; College of Engineering; Graduate School of Sciences and Engineering; 109820; N/A
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    Multiscale simulations of partially disordered systems
    (2017) Globisch, C.; Peter, C.; N/A; Department of Mechanical Engineering; Dalgıçdır, Cahit; Sayar, Mehmet; PhD Student; Faculty Member; Department of Mechanical Engineering; Graduate School of Sciences and Engineering; College of Engineering; N/A; 109820
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    Adsorption, folding, and packing of an amphiphilic peptide at the air/water interface
    (amer Chemical Soc, 2012) N/A; Department of Mechanical Engineering; Engin, Özge; Sayar, Mehmet; Master Student; Faculty Member; Department of Mechanical Engineering; Graduate School of Sciences and Engineering, College of Engineering; N/A; 109820
    Peptide oligomers play an essential role as model compounds for identifying key motifs in protein structure formation and protein aggregation. Here, we present our results, based on extensive molecular dynamics simulations, on adsorption, folding, and packing within a surface monolayer of an amphiphilic peptide at the air/water interface. Experimental results suggest that these molecules spontaneously form ordered monolayers at the interface, Adopting a beta-hairpin-like structure within the surface layer. Our results reveal that the beta-hairpin structure can be observed both in bulk and at the air/water interface. However, the presence of an interface leads to ideal partitioning of the hydrophobic and hydrophilic residues, and therefore reduces the conformational space for the molecule and increases the stability of the hairpin structure. We obtained the adsorption free energy of a single beta-hairpin at the air/water interface, and analyzed the enthalpic and entropic contributions. the adsorption process is favored by two main factors: (1) Free-energy reduction due to desolvation of the hydrophobic side chains of the peptide and release of the water molecules which form a cage around these hydrophobic groups in bulk water. (2) Reduction of the total air/water contact area at the interface upon adsorption of the peptide amphiphile. By performing mutations on the original molecule, we demonstrated the relative role of key design features of the peptide. Finally, by analyzing the potential of mean force among two peptides at the interface, we investigated possible packing mechanisms for these molecules within the surface monolayer.
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    Finite-size polyelectrolyte bundles at thermodynamic equilibrium
    (2007) Holm, Christian; Department of Mechanical Engineering; Sayar, Mehmet; Faculty Member; Department of Mechanical Engineering; College of Engineering; 109820
    We present the results of extensive computer simulations performed on solutions of monodisperse charged rod-like polyelectrolytes in the presence of trivalent counterions. To overcome energy barriers we used a combination of parallel tempering and hybrid Monte Carlo techniques. Our results show that for small values of the electrostatic interaction the solution mostly consists of dispersed single rods. The potential of mean force between the polyelectrolyte monomers yields an attractive interaction at short distances. For a range of larger values of the Bjerrum length, we find finite-size polyelectrolyte bundles at thermodynamic equilibrium. Further increase of the Bjerrum length eventually leads to phase separation and precipitation. We discuss the origin of the observed thermodynamic stability of the finite-size aggregates. 
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    Representing environment-induced helix-coil transitions in a coarse grained peptide model
    (Springer, 2016) Dalgıçdir, Cahit; Globisch, Christoph; Peter, Christine; Department of Mechanical Engineering; Sayar, Mehmet; Faculty Member; Department of Mechanical Engineering; College of Engineering; 109820
    Coarse grained (CG) models are widely used in studying peptide self-assembly and nanostructure formation. One of the recurrent challenges in CG modeling is the problem of limited transferability, for example to different thermodynamic state points and system compositions. Understanding transferability is generally a prerequisite to knowing for which problems a model can be reliably used and predictive. For peptides, one crucial transferability question is whether a model reproduces the molecule's conformational response to a change in its molecular environment. This is of particular importance since CG peptide models often have to resort to auxiliary interactions that aid secondary structure formation. Such interactions take care of properties of the real system that are per se lost in the coarse graining process such as dihedral-angle correlations along the backbone or backbone hydrogen bonding. These auxiliary interactions may then easily overstabilize certain conformational propensities and therefore destroy the ability of the model to respond to stimuli and environment changes, i.e. they impede transferability. In the present paper we have investigated a short peptide with amphiphilic EALA repeats which undergoes conformational transitions between a disordered and a helical state upon a change in pH value or due to the presence of a soft apolar/polar interface. We designed a base CG peptide model that does not carry a specific (backbone) bias towards a secondary structure. This base model was combined with two typical approaches of ensuring secondary structure formation, namely a Ca-Ca-Ca-Ca pseudodihedral angle potential or a virtual site interaction that mimics hydrogen bonding. We have investigated the ability of the two resulting CG models to represent the environment-induced conformational changes in the helix-coil equilibrium of EALA. We show that with both approaches a CG peptide model can be obtained that is environment-transferable and that correctly represents the peptide's conformational response to different stimuli compared to atomistic reference simulations. The two types of auxiliary interactions lead to different kinetic behavior as well as to different structural properties for fully formed helices and folding intermediates, and we discuss the advantages and disadvantages of these approaches.
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    Conformation and aggregation of LKα14 peptide in bulk water and at the air/water ınterface
    (Amer Chemical Soc, 2015) N/A; Department of Mechanical Engineering; Dalgıçdır, Cahit; Sayar, Mehmet; PhD Student; Faculty Member; Department of Mechanical Engineering; Graduate School of Sciences and Engineering; College of Engineering; N/A; 109820
    Historically, the protein folding problem has mainly been associated with understanding the relationship between amino acid sequence and structure. However, it is known that both the conformation of individual molecules and their aggregation strongly depend on the environmental conditions. Here, we study the aggregation behavior of the model peptide LK alpha 14 (with amino acid sequence LKKLLKLLKKLLKL) in bulk water and at the air/water interface. We start by a quantitative analysis of the conformational space of a single LK alpha 14 in bulk water. Next, in order to analyze the aggregation tendency of LK alpha 14, by using the umbrella sampling technique we calculate the potential of mean force for pulling a single peptide from an n-molecule aggregate. In agreement with the experimental results, our calculations yield the optimal aggregate size as four. This equilibrium state is achieved by two opposing forces: Coulomb repulsion between the lysine side chains and the reduction of solvent accessible hydrophobic surface area upon aggregation. At the vacuum/water interface, however, even dimers of LK alpha 14 become marginally stable, and any larger aggregate falls apart instantaneously. Our results indicate that even though the interface is highly influential in stabilizing the a-helix conformation for a single molecule, it significantly reduces the attraction between two LK alpha 14 peptides, along with their aggregation tendency.