Dimitrios Morikis

University of California, Riverside, Riverside, California, United States

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Publications (108)305.69 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Compstatin peptides are complement inhibitors that bind and inhibit cleavage of complement C3. Peptide binding is enhanced by hydrophobic interactions, however poor solubility promotes aggregation in aqueous environments. We have designed new compstatin peptides derived from the W4A9 sequence (Ac-ICVWQDWGAHRCT-NH2, cyclized between C2 and C12), based on structural, computational, and experimental studies. Furthermore, we developed and utilized a computational framework for the design of peptides containing non- natural amino acids. These new compstatin peptides contain polar N-terminal extensions and non-natural amino acid substitutions at positions 4 and 9. Peptides with alpha-modified non- natural alanine analogs at position 9, as well as peptides containing only N-terminal polar extensions, exhibited similar activity compared to W4A9, as quantified via ELISA, hemolytic, and cell-based assays, and showed improved solubility, as measured by UV absorbance and reverse-phase HPLC experiments. Due to their potency and solubility, these peptides are promising candidates for therapeutic development in numerous complement-mediated diseases.
    Journal of medicinal chemistry. 12/2014;
  • Rohith R Mohan, Ronald D Gorham, Dimitrios Morikis
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    ABSTRACT: The C3d:CR2(SCR1-2) interaction plays an important role in bridging innate and adaptive immunity, leading to enhanced antibody production at sites of complement activation. Over the past decade, there has been much debate over the binding mode of this interaction. An initial cocrystal structure (PDB: 1GHQ) was published in 2001, in which the only interactions observed were between the SCR2 domain of CR2 and a side-face of C3d whereas a cocrystal structure (PDB: 3OED) published in 2011 showed both the SCR1 and SCR2 domains of CR2 interacting with an acidic patch on the concave surface of C3d. The initial 1GHQ structure is at odds with the majority of existing biochemical data and the publication of the 3OED structure renewed uncertainty regarding the physiological relevance of 1GHQ, suggesting that crystallization may have been influenced by the presence of zinc acetate in the crystallization process. In our study, we used a variety of computational approaches to gain insight into the binding mode between C3d and CR2 and demonstrate that the binding site at the acidic patch (3OED) is electrostatically more favorable, exhibits better structural and dissociative stability, specifically at the SCR1 domain, and has higher binding affinity than the 1GHQ binding mode. We also observe that nonphysiological zinc ions enhance the formation of the C3d:CR2 complex at the side face of C3d (1GHQ) through increases in electrostatic favorability, intermolecular interactions, dissociative character and overall energetic favorability. These results provide a theoretical basis for the association of C3d:CR2 at the acidic cavity of C3d and provide an explanation for binding of CR2 at the side face of C3d in the presence of nonphysiological zinc ions. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Molecular immunology. 11/2014;
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    ABSTRACT: The complement cascade is a highly sophisticated network of proteins that are well regulated and directed in response to invading pathogens or tissue injury. Complement C3a and C5a are key mediators produced by this cascade, and their dysregulation has been linked to a plethora of inflammatory and autoimmune diseases. Consequently, this has stimulated interest in the development of ligands for the receptors for these complement peptides, C3a receptor, and C5a1 (C5aR/CD88). In this study we used computational methods to design novel C5a1 receptor ligands. However, functional screening in human monocyte-derived macrophages using the xCELLigence label-free platform demonstrated altered specificity of our ligands. No agonist/antagonist activity was observed at C5a1, but we instead saw that the ligands were able to partially agonize the closely related complement receptor C3a receptor. This was verified in the presence of C3a receptor antagonist SB 290157 and in a stable cell line expressing either C5a1 or C3a receptor alone. C3a agonism has been suggested to be a potential treatment of acute neutrophil-driven traumatic pathologies, and may have great potential as a therapeutic avenue in this arena.
    European journal of Pharmacology. 10/2014;
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    ABSTRACT: The complement system surveillance in the host is effective in controlling viral propagation. Consequently, to subvert this effector mechanism, viruses have developed a series of adaptations. One among these is encoding mimics of host regulators of complement activation (RCA) which help viruses to avoid being labeled as ‘foreign’ and protect them from complement-mediated neutralization and complement-enhanced antiviral adaptive immunity. In this review, we provide an overview on the structure, function and evolution of viral RCA proteins.
    Molecular Immunology. 10/2014; 61(2):89–99.
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    ABSTRACT: The complement system surveillance in the host is effective in controlling viral propagation. Consequently, to subvert this effector mechanism, viruses have developed a series of adaptations. One among these is encoding mimics of host regulators of complement activation (RCA) which help viruses to avoid being labeled as 'foreign' and protect them from complement-mediated neutralization and complement-enhanced antiviral adaptive immunity. In this review, we provide an overview on the structure, function and evolution of viral RCA proteins.
    Molecular immunology. 06/2014;
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    ABSTRACT: SAME SAME Cell and Molecular Biology section/symposium Oral/poster presentation Student The role of AlgX carbohydrate-binding module during alginate biosynthesis in Pseudomonas aeruginosa, Cystic fibrosis is a chronic, progressive, and often fatal genetic inherited disease caused by mutations in the gene that encodes the cystic fibrosis transmembrane conductance regulator (CFTR). Alginate or mucoid encapsulated Pseudomonas aeruginosa is the causative agent of respiratory insufficiency and failure in patients with cystic fibrosis. We have previously reported that AlgX is a protein required for alginate biosynthesis. Recently, AlgX has been reported to play a role in the modification of alginate through acetylation. In this study, we show that the absence of AlgX resulted in the loss of mucoidy due to the degradation of nascent alginate by the alginate lyase, AlgL. Using computational molecular docking studies and alginate affinity assay, we show that AlgX binds alginate via the carbohydrate-binding module located in the C-terminal region. Alanine mutations of the predicted amino acid residues that interact with alginate suggest that K338, R370, T372, and R380 are important for alginate binding. Alginate rescue assay by in trans expression of mutant AlgX in a chromosomal algX deleted P. aeruginosa mutant confirms the importance of these amino acid residues during alginate biosynthesis. In summary, these studies suggest that AlgX protects the alginate polymers from AlgL degradation, binds alginate via the carbohydrate-binding module, and is conceivably located in the biosynthetic scaffold serving as an appendage to the alginate acetylation machinery. In conclusion, AlgX binds alginate via the carbohydrate-binding module and is required for alginate biosynthesis and modification. Abstract contains 236/250 words
    American Association for the Advancement of Science, Riverside, CA; 06/2014
  • Yan Liu, Chris A Kieslich, Dimitrios Morikis, Jiayu Liao
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    ABSTRACT: SUMOylation, one of the most important protein post-translational modifications, plays critical roles in a variety of physiological and pathological processes. SENP (Sentrin/SUMO-specific protease), a family of SUMO-specific proteases, is responsible for the processing of pre-SUMO and removal of SUMO from conjugated substrates. SUMO4, the latest discovered member in the SUMO family, has been found as a type 1 diabetes susceptibility gene and its maturation is not understood so far. Despite the 14 amino acid differences between pre-SUMO4 and SUMO2, pre-SUMO4 is not processed by SENP2 but pre-SUMO2 does. A novel interdisciplinary approach involving computational modeling and a FRET-based protease assay was taken to engineer pre-SUMO4 as a substrate of SENP2. Given the difference in net charge between pre-SUMO4 and pre-SUMO2, the computational framework analysis of electrostatic similarities of proteins was applied to determine the contribution of each ionizable amino acid in a model of SENP2-(pre-SUMO4) binding, and to propose pre-SUMO4 mutations. The specificities of the SENP2 toward different pre-SUMO4 mutants were determined using a quantitative FRET assay by characterizing the catalytic efficiencies (kcat/KM). A single amino acid mutation made pre-SUMO4 amenable to SENP2 processing and a combination of two amino acid mutations made it highly accessible as SENP2 substrate. The combination of the two approaches provides a powerful protein engineering tool for future SUMOylation studies.
    Protein Engineering Design and Selection 04/2014; 27(4):117-26. · 2.59 Impact Factor
  • Ronald D Gorham, Wilson Rodriguez, Dimitrios Morikis
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    ABSTRACT: Staphylococcus aureus expresses numerous virulence factors that aid in immune evasion. The four-domain staphylococcal immunoglobulin binding (Sbi) protein interacts with complement component 3 (C3) and its thioester domain (C3d)-containing fragments. Recent structural data suggested two possible modes of binding of Sbi domain IV (Sbi-IV) to C3d, but the physiological binding mode remains unclear. We used a computational approach to provide insight into the C3d-Sbi-IV interaction. Molecular dynamics (MD) simulations showed that the first binding mode (PDB code 2WY8) is more robust than the second (PDB code 2WY7), with more persistent polar and nonpolar interactions, as well as conserved interfacial solvent accessible surface area. Brownian dynamics and steered MD simulations revealed that the first binding mode has faster association kinetics and maintains more stable intermolecular interactions compared to the second binding mode. In light of available experimental and structural data, our data confirm that the first binding mode represents Sbi-IV interaction with C3d (and C3) in a physiological context. Although the second binding mode is inherently less stable, we suggest a possible physiological role. Both binding sites may serve as a template for structure-based design of novel complement therapeutics.
    Biophysical Journal 03/2014; 106(5):1164-1173. · 3.67 Impact Factor
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    ABSTRACT: The complement protein C5a acts by primarily binding and activating the G-protein coupled C5a receptor C5aR (CD88), and is implicated in many inflammatory diseases. The cyclic hexapeptide PMX53 (sequence Ace-Phe-[Orn-Pro-dCha-Trp-Arg]) is a full C5aR antagonist of nanomolar potency, and is widely used to study C5aR function in disease.
    BMC Biophysics 01/2014; 7:5. · 1.67 Impact Factor
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    ABSTRACT: We have used a novel human retinal pigmented epithelial (RPE) cell-based model that mimics drusen biogenesis and the pathobiology of age-related macular degeneration to evaluate the efficacy of newly designed peptide inhibitors of the complement system. The peptides belong to the compstatin family and, compared to existing compstatin analogs, have been optimized to promote binding to their target, complement protein C3, and to enhance solubility by improving their polarity/hydrophobicity ratios. Based on analysis of molecular dynamics simulation data of peptide-C3 complexes, novel binding features were designed by introducing intermolecular salt bridge-forming arginines at the N-terminus and at position -1 of N-terminal dipeptide extensions. Our study demonstrates that the RPE cell assay has discriminatory capability for measuring the efficacy and potency of inhibitory peptides in a macular disease environment.
    Experimental Eye Research 08/2013; · 3.03 Impact Factor
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    ABSTRACT: Despite its sequence variability and structural flexibility, the V3 loop of the HIV-1 envelope glycoprotein gp120 is capable of recognizing cell-bound co-receptors CCR5 and CXCR4 and infecting cells. Viral selection of CCR5 is associated with the early stages of infection, and transition to selection of CXCR4 indicates disease progression. We have developed a predictive statistical model for co-receptor selectivity that uses the discrete property of net charge and the binary co-receptor preference markers of the N6X7[T/S]8X9 glycosylation motif and 11/24/25 positive amino acid rule. The model is based on analysis of 2,054 V3 loop sequences from patient data and allows us to infer the most likely state of the disease from physicochemical characteristics of the sequences. The performance of the model is comparable to established sequence-based predictive methods, and may be used in combination with other methods as a supportive diagnostic for co-receptor selection. This model may be used for personalized medical decisions in administering co-receptor-specific therapies.
    AIDS research and human retroviruses 06/2013; · 2.18 Impact Factor
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    Molecular Immunology. 01/2013; 53(s 1–2):173–174.
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    Chris A Kieslich, Dimitrios Morikis
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    ABSTRACT: The interaction between complement fragment C3d and complement receptor 2 (CR2) is a key aspect of complement immune system activation, and is a component in a link between innate and adaptive immunities. The complement immune system is an ancient mechanism for defense, and can be found in species that have been on Earth for the last 600 million years. However, the link between the complement system and adaptive immunity, which is formed through the association of the B-cell co-receptor complex, including the C3d-CR2 interaction, is a much more recent adaptation. Human C3d and CR2 have net charges of -1 and +7 respectively, and are believed to have evolved favoring the role of electrostatics in their functions. To investigate the role of electrostatics in the function and evolution of human C3d and CR2, we have applied electrostatic similarity methods to identify regions of evolutionarily conserved electrostatic potential based on 24 homologues of complement C3d and 4 homologues of CR2. We also examine the effects of structural perturbation, as introduced through molecular dynamics and mutations, on spatial distributions of electrostatic potential to identify perturbation resistant regions, generated by so-called electrostatic "hot-spots". Distributions of electrostatic similarity based on families of perturbed structures illustrate the presence of electrostatic "hot-spots" at the two functional sites of C3d, while the surface of CR2 lacks electrostatic "hot-spots" despite its excessively positive nature. We propose that the electrostatic "hot-spots" of C3d have evolved to optimize its dual-functionality (covalently attaching to pathogen surfaces and interaction with CR2), which are both necessary for the formation B-cell co-receptor complexes. Comparison of the perturbation resistance of the electrostatic character of the homologues of C3d suggests that there was an emergence of a new role of electrostatics, and a transition in the function of C3d, after the divergence of jawless fish.
    PLoS Computational Biology 12/2012; 8(12):e1002840. · 4.87 Impact Factor
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    ABSTRACT: Targeting the complement component 3a receptor (C3aR) with selective agonists or antagonists is believed to be a viable therapeutic option for several diseases such as stroke, heart attack, reperfusion injuries, and rheumatoid arthritis. We designed a number of agonists, partial agonists, and antagonists of C3aR using our two-stage de novo protein design framework. Of the peptides tested using a degranulation assay in C3aR-transfected rat basophilic leukemia cells, two were prominent agonists (EC(50) values of 25.3 and 66.2 nM) and two others were partial agonists (IC(50) values of 15.4 and 26.1 nM). Further testing of these lead compounds in a calcium flux assay in U937 cells yielded similar results although with reduced potencies compared to transfected cells. The partial agonists also displayed full antagonist activity when tested in a C3aR inhibition assay. In addition, the electrostatic potential profile was shown to potentially discriminate between full agonists and partial agonists.
    Journal of Medicinal Chemistry 04/2012; 55(9):4159-68. · 5.61 Impact Factor
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    ABSTRACT: We report the computational and rational design of new generations of potential peptide-based inhibitors of the complement protein C3 from the compstatin family. The binding efficacy of the peptides is tested by extensive molecular dynamics-based structural and physicochemical analysis, using 32 atomic detail trajectories in explicit water for 22 peptides bound to human, rat or mouse target protein C3, with a total of 257 ns. The criteria for the new design are: (i) optimization for C3 affinity and for the balance between hydrophobicity and polarity to improve solubility compared to known compstatin analogs; and (ii) development of dual specificity, human-rat/mouse C3 inhibitors, which could be used in animal disease models. Three of the new analogs are analyzed in more detail as they possess strong and novel binding characteristics and are promising candidates for further optimization. This work paves the way for the development of an improved therapeutic for age-related macular degeneration, and other complement system-mediated diseases, compared to known compstatin variants.
    Chemical Biology &amp Drug Design 01/2012; 79(5):703-18. · 2.47 Impact Factor
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    ABSTRACT: The V3 loop of the glycoprotein gp120 of HIV-1 plays an important role in viral entry into cells by utilizing as coreceptor CCR5 or CXCR4, and is implicated in the phenotypic tropisms of HIV viruses. It has been hypothesized that the interaction between the V3 loop and CCR5 or CXCR4 is mediated by electrostatics. We have performed hierarchical clustering analysis of the spatial distributions of electrostatic potentials and charges of V3 loop structures containing consensus sequences of HIV-1 subtypes. Although the majority of consensus sequences have a net charge of +3, the spatial distribution of their electrostatic potentials and charges may be a discriminating factor for binding and infectivity. This is demonstrated by the formation of several small subclusters, within major clusters, which indicates common origin but distinct spatial details of electrostatic properties. Some of this information may be present, in a coarse manner, in clustering of sequences, but the spatial details are largely lost. We show the effect of ionic strength on clustering of electrostatic potentials, information that is not present in clustering of charges or sequences. We also make correlations between clustering of electrostatic potentials and net charge, coreceptor selectivity, global prevalence, and geographic distribution. Finally, we interpret coreceptor selectivity based on the N6X7T8|S8X9 sequence glycosylation motif, the specific positive charge location according to the 11/24/25 rule, and the overall charge and electrostatic potential distribution. We propose that in addition to the sequence and the net charge of the V3 loop of each subtype, the spatial distributions of electrostatic potentials and charges may also be important factors for receptor recognition and binding and subsequent viral entry into cells. This implies that the overall electrostatic potential is responsible for long-range recognition of the V3 loop with coreceptors CCR5/CXCR4, whereas the charge distribution contributes to the specific short-range interactions responsible for the formation of the bound complex. We also propose a scheme for coreceptor selectivity based on the sequence glycosylation motif, the 11/24/25 rule, and net charge.
    BMC Biophysics 01/2012; 5:3. · 1.67 Impact Factor
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    ABSTRACT: The V3 loop of the glycoprotein 120 (gp120) is a contact point for cell entry of HIV-1 leading to infection. Despite sequence variability and lack of specific structure, the highly flexible V3 loop possesses a well-defined role in recognizing and selecting cell-bound coreceptors CCR5 and CXCR4 through a mechanism of charge complementarity. We have performed two independent molecular dynamics (MD) simulations to gain insights into the dynamic character of two V3 loops with slightly different sequences, but significantly different starting crystallographic structures. We have identified highly populated trajectory-specific salt bridges between oppositely charged stem residues Arg9 and Glu25 or Asp29. The two trajectories share nearly identical correlated motions within the simulations, despite their different overall structures. High occupancy salt bridges play a key role in the major cross-correlated motions in both trajectories, and may be responsible for transient structural stability in preparation for coreceptor binding. In addition, the two V3 loops visit conformations with similarities in spatial distributions of electrostatic potentials, despite their inherent flexibility, which may play a role in coreceptor recognition. It is plausible that cooperativity between overall electrostatic potential, charged residue interactions, and correlated motions could be associated with a coreceptor selection and binding.
    PLoS ONE 01/2012; 7(11):e49925. · 3.53 Impact Factor
  • Biophysical Journal 01/2012; 102(3):64-. · 3.67 Impact Factor
  • Chris A. Kieslich, Dimitrios Morikis
    Biophysical Journal 01/2012; 102(3):463-. · 3.67 Impact Factor

Publication Stats

2k Citations
305.69 Total Impact Points

Institutions

  • 2001–2014
    • University of California, Riverside
      • • Department of Bioengineering
      • • Center for Bioengineering Research
      • • Department of Botany and Plant Sciences
      • • Department of Chemistry
      • • Department of Chemical and Environmental Engineering
      Riverside, California, United States
  • 2007–2011
    • University of Cyprus
      • Department of Physics
      Nicosia, Nicosia District, Cyprus
  • 2003–2011
    • Princeton University
      • Department of Chemical and Biological Engineering
      Princeton, New Jersey, United States
  • 2003–2010
    • National Centre For Cell Science, Pune
      Poona, Mahārāshtra, India
  • 2006–2009
    • CSU Mentor
      Long Beach, California, United States
    • Keck Graduate Institute
      Claremont, California, United States
  • 2001–2008
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States
  • 2005
    • Hospital of the University of Pennsylvania
      • Department of Pathology and Laboratory Medicine
      Philadelphia, PA, United States
  • 2000–2004
    • University of Pennsylvania
      • Department of Pathology and Laboratory Medicine
      Philadelphia, PA, United States
  • 2000–2003
    • University of California, San Diego
      • Department of Chemistry and Biochemistry
      San Diego, CA, United States
  • 1998
    • Sanford-Burnham Medical Research Institute
      La Jolla, California, United States
  • 1994–1996
    • The Scripps Research Institute
      • Department of Cell and Molecular Biology
      La Jolla, CA, United States
  • 1989–1992
    • Northeastern University
      • Department of Physics
      Boston, MA, United States
  • 1990
    • University of Illinois, Urbana-Champaign
      • Department of Biochemistry
      Urbana, IL, United States