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Electrostatic Properties of Protein-Protein Complexes

Petras J. Kundrotas, Emil Alexov
2006 Biophysical Journal  
Alexov, unpublished) , which, after applying some selection rules, provided us with a set of 37 protein-protein complexes.  ...  Alexov, unpublished) and here we mention only that it contains 251 two-chain complexes and 708 two-domain structures with experimentally determined 3D structures.  ... 
doi:10.1529/biophysj.106.086025 pmid:16782791 pmcid:PMC1544298 fatcat:jz25cdto6bglpkz3nuublaxgdy

Navigating through Genomics Data to Deliver Testable Predictions

Emil Alexov
2015 Human Mutation  
Emil Alexov Department of Physics Clemson University, Clemson, South Carolina Shotgun Approach to Functional Annotation of Genes As clinical disease predisposition testing becomes more common, the  ... 
doi:10.1002/humu.22733 fatcat:rybg7gvpozfsheceugj55g2ecq

An Ensemble Approach to Predict the Pathogenicity of Synonymous Variants

Satishkumar Ranganathan Ganakammal, Emil Alexov
2020 Genes  
Single-nucleotide variants (SNVs) are a major form of genetic variation in the human genome that contribute to various disorders. There are two types of SNVs, namely non-synonymous (missense) variants (nsSNVs) and synonymous variants (sSNVs), predominantly involved in RNA processing or gene regulation. sSNVs, unlike missense or nsSNVs, do not alter the amino acid sequences, thereby making challenging candidates for downstream functional studies. Numerous computational methods have been
more » ... to evaluate the clinical impact of nsSNVs, but very few methods are available for understanding the effects of sSNVs. For this analysis, we have downloaded sSNVs from the ClinVar database with various features such as conservation, DNA-RNA, and splicing properties. We performed feature selection and implemented an ensemble random forest (RF) classification algorithm to build a classifier to predict the pathogenicity of the sSNVs. We demonstrate that the ensemble predictor with selected features (20 features) enhances the classification of sSNVs into two categories, pathogenic and benign, with high accuracy (87%), precision (79%), and recall (91%). Furthermore, we used this prediction model to reclassify sSNVs with unknown clinical significance. Finally, the method is very robust and can be used to predict the effect of other unknown sSNVs.
doi:10.3390/genes11091102 pmid:32967157 pmcid:PMC7565489 fatcat:qzixkbxgevdflklaleih5xosfu

In Silico Investigation of Mutability of Spermine Synthase

Zhe Zhang, Charles Schwartz, Emil Alexov
2011 Biophysical Journal  
Spermine Synthase (SMS) is an enzyme which controls spermidine/spermine concentrations, both of which are polyamines playing an important role for cell development. Recently we have investigated the effect of missense mutations (G56S, V132G and I150T) known to cause Synder-Robinson Syndrome (SRS) on SMS stability and dynamics. Here we extend our study to predict the mutability of these clinically observed sites. For this purpose, we substitute in silico the wild type residue at each site (G56,
more » ... 132 and I150) with all other 19 amino acids and calculate the effect of stability and ionizations states of SMS. We show that mutations at site 150 are expected to greatly disrupt wide type function regardless of the amino acid substitution. Such site is termed intolerable site and is characterized with very low mutability. In contrast, site V132, despite being at the dimer interface is predicted to tolerate mutations and to be quite mutable. The G56 site is in the middle of the spectra, since some of the mutations are predicted to have significant effect on dimer stability, which in turn is crucial for the function of SMS. The performed analysis shows that mutability depends on the detail of the structural and functional factors and can not be predicted based on conservation of wild type properties alone. This work was supported by awards from NLM/NIH, grant numbers 1R03LM009748 and 1R03LM009748-S1. 1740-Pos Board B650 Properties of Lipid a Bilayers Analyzed by Molecular Dynamics Simulations Danielle Stuhlsatz, Richard Venable, Wonpil Im. Lipopolysaccharide (LPS), responsible for the toxicity of Gram-negative bacteria, is made up of three regions: the O antigen, the core, and the innermost lipid A. Lipid A is the lipid component whose hydrophobic nature allows LPS to anchor to the bacteria outer membrane. Utilizing the latest C36 CHARMM lipid and carbohydrate force field, we have constructed a lipid A molecule of E. coli. Various bilayer systems were then constructed six different conditions: 1) CaCl 2 at 80% water and at 303K or 323K, 2) KCl at 80% water at 303K or 323K, and 3) KCl at 40% water at 303K or 323K. We are currently running molecular dynamics simulations of these systems. The simulation results will be discussed in terms of how different temperatures, ratios of water molecules to lipids, and charged ions affects the lipid A bilayer properties such as surface area, ion location, chain order, bilayer thickness and shape, and the carbohydrate conformations. The results from these simulations will be also compared with available experimental data. This work will be the basis of the future simulations of the complex glycolipid simulations such as LPS, and membrane protein simulations in more native bilayer environments. Chlamydia trachomatis is an obligate intracellular human pathogen which can cause trachoma, conjunctivitis, infection of urogenital system and lymphogranuloma-venereum in humans. Preventive measures have recently focused on production of vaccine using the variable domain (VD) extracellular loops of the major outer membrane protein (MOMP). MOMP's crystal structure has not been determined, but serious efforts have been made to propose its structure and function experimentally and theoretically. Our objective is to utilize this information to obtain a consistent secondary and tertiary structure. MOMP functions as general diffusion porin having b-barrel structure. We predict 16 b-stranded transmembrane sheets, and variable domains at proper positions, consistent with available experimental data. Having no sequence similarity of MOMP with other porin proteins, a threading technique was utilized for structure prediction with the outer membrane porin protein (2OMF) of E.Coli as a template. Using hand-threading, MOMP sequence was aligned along the structure of 2OMF. The Modeler program was used to build a final structure (pre-refined). We selected a fragment with five b-sheets and loops containing VD-3 and VD-4. This fragment was further refined (post), using simulations, to get full length b-sheets in a realistic Chlamydial membrane. Our current objective is to continue molecular dynamics (MD) simulations to check the consistency of these (pre-and post-refined) fragments. Implicit water simulations of both refined fragments resulted in loss of secondary and tertiary structure, while MD simulations of post-refined fragment in Chlamydial membrane were stable. This implies that vaccine development requires delivery vehicles that are lipid-like to maintain the stability of these protein fragments. Moreover, future MD simulations of both fragments in a Chlamydial membrane will improve our understanding of stable loop conformations and guide experimentalists in developing a peptide-based vaccine. 1742-Pos Board B652 Development of a Novel Algorithm for Identifying Transcription Factor Binding Motifs in the Genome DNA Sequences Ryo Nakaki, Masaru Tateno. Finding of transcription factor binding motifs (TFBMs) is essential for identifying the detailed transcriptional regulation networks. In this study, we developed a novel algorithm for identifying the TFBMs by using the genome DNA sequence. We compared the accuracy of our algorithm with that of the conventional ones by exploiting ChIP-on-chip genome DNA sequence fragments, as test data, which were extracted by treatments to induce specific TFBMs of S. cerevisiae and human estrogen receptor (ER) expressed in human MCF-7 breast cancer cells. As a result of our calculation of the S. cerevisiae data, our algorithm identified 69 % known TFBMs from 65 datasets, each of which is corresponding to distinct TFBMs. In contrast, the conventional algorithms identified 63 % (BioProspector), 49 % (MDscan), and 52 % (MEME); here, the default parameter set was used for each identification system. Also, for ER elements (ERE), our algorithm exactly identified the position-specific scoring matrix (PSSM) using the human ER data, whereas the conventional algorithms did not. If single sequence repeats (SSLs) are removed from the ER data, BioProspector identified the PSSM of the human ERE. Accordingly, our system is expected to identify unknown TFBMs as well as known ones using genome DNA sequences without editing/tuning the parameter set used in our identification system. Further, identification of co-regulated known/unknown transcription factors is now going on by using experimental data obtained by DNA microarray techniques and the cap analysis gene expression (CAGE) systems. 1743-Pos Board B653 Correlating in Vitro Measurements of Protein-DNA Binding Affinities with in Vivo Repression and Impact on the Growth Rate of the Host Organism Liskin Swint-Kruse, Michael Manley, Sudheer Tungtur, Hongli Zhan. In order to fully decode the information of patient genomes, we must determine which protein polymorphisms alter function. One resource for addressing this question is the sequence set of naturally occurring homologs. Sequence comparisons easily identify conserved positions, which usually cannot be changed without consequence. However, the impact of changing nonconserved positions is less-easily predicted. We have devised a model system for testing computational identifications of important nonconserved positions and measuring the functional impact from amino acid substitutions at these positions. The model system is based on chimeric proteins of the LacI/GalR family; functional change can be detected as either altered in vivo repression or altered in vitro DNA binding properties. For this system to accurately model a naturally-evolving system, an observed change in repression must be large enough to impact the growth of the host organism. Here, we use a series of point mutations in an engineered LacI/GalR transcription repressor to correlate altered in vivo repression with thermodynamic measurements of DNA binding affinities and bacterial growth rates. Results will determine whether most changes in repression are due to changes in DNA-binding affinity for the in vivo operator DNA binding site, and will determine how large a change in repression is required to alter bacterial life cycles. With the availability of KOMP mutant mice, RNAi and lower cost of whole genome microarrays and sequencing techniques, a new generation of multiknockout comparative studies will be feasible and highly desirable in identifying genetic functional and interactive relationships. Nevertheless, given the large number of molecular factors occurring in a system level and varying with time, precise gene interaction identification is a formidable challenge. Many existing computational approaches are limited to static and/or relatively simple gene networks. Herein, we developed a new algorithm to discover timedependent, complex gene regulations from multiple perturbation data. The approach is based on Dynamic Bayesian Networks (DBN) in conjunction with an improved Markov-Chain-Monte-Carlo (MCMC) sampling. DBN permits temporal pattern exploration and a system level data integration. We used a dataderived Proposal Matrix (DPM) that estimates the significance of gene relationships to guide MCMC search more efficiently. Further, we consolidated prior Monday, March 7, 2011 321a
doi:10.1016/j.bpj.2010.12.1951 fatcat:el6hq4hvfzfynnqdeczczd7mo4

Progress in developing Poisson-Boltzmann equation solvers

Chuan Li, Lin Li, Marharyta Petukh, Emil Alexov
2013 Molecular Based Mathematical Biology  
This review outlines the recent progress made in developing more accurate and efficient solutions to model electrostatics in systems comprised of bio-macromolecules and nano-objects, the last one referring to objects that do not have biological function themselves but nowadays are frequently used in biophysical and medical approaches in conjunction with bio-macromolecules. The problem of modeling macromolecular electrostatics is reviewed from two different angles: as a mathematical task
more » ... the specific definition of the system to be modeled and as a physical problem aiming to better capture the phenomena occurring in the real experiments. In addition, specific attention is paid to methods to extend the capabilities of the existing solvers to model large systems toward applications of calculations of the electrostatic potential and energies in molecular motors, mitochondria complex, photosynthetic machinery and systems involving large nano-objects.
doi:10.2478/mlbmb-2013-0002 pmid:24199185 pmcid:PMC3816640 fatcat:3v7q5ehr3faqpmkcokrgr5lhne

On the role of electrostatics in protein–protein interactions

Zhe Zhang, Shawn Witham, Emil Alexov
2011 Physical Biology  
The role of electrostatics on protein-protein interactions and binding is reviewed in this article. A brief outline of the computational modeling, in the framework of continuum electrostatics, is presented and basic electrostatic effects occurring upon the formation of the complex are discussed. The role of the salt concentration and pH of the water phase on protein-protein binding free energy is demonstrated and indicates that the increase of the salt concentration tends to weaken the binding,
more » ... an observation that is attributed to the optimization of the charge-charge interactions across the interface. It is pointed out that the pH-optimum (pH of optimal binding affinity) varies among the protein-protein complexes, and perhaps is a result of their adaptation to particular subcellular compartment. At the end, the similarities and differences between heteroand homo-complexes are outlined and discussed with respect to the binding mode and charge complementarity.
doi:10.1088/1478-3975/8/3/035001 pmid:21572182 pmcid:PMC3137121 fatcat:wacxnmp43bdonfyema3r5uvylu

Enhancing Human Spermine Synthase Activity by Site Directed Mutations

Zhe Zhang, Anthony Pegg, Yoshihiko Ikeguchi, Emil Alexov
2013 Biophysical Journal  
Enhancing Human Spermine Synthase Activity by Site Directed Mutations Zhe Zhang 1,2 , Anthony Pegg 3 , Yoshihiko Ikeguchi 4 , Emil Alexov 1 . 1 Clemson University, Clemson, SC, USA, 2 University of Paris  ... 
doi:10.1016/j.bpj.2012.11.2117 fatcat:oitituonjngltjbacgkjcy7dce

Modeling Electrostatic Force in Protein-Protein Recognition

H. B. Mihiri Shashikala, Arghya Chakravorty, Emil Alexov
2019 Frontiers in Molecular Biosciences  
It is the major component determining pKa values of ionizable groups in proteins and DNAs/RNAs Onufriev and Alexov, 2013; Wang et al., 2015; Pahari et al., 2018) .  ...  Depending on the charge distribution, both the net charge and the charge at the binding interfaces, the Coulombic interactions may be favorable or not (Kundrotas and Alexov, 2006; Teng et al., 2009 ).  ...  Copyright © 2019 Shashikala, Chakravorty and Alexov. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY).  ... 
doi:10.3389/fmolb.2019.00094 pmid:31608289 pmcid:PMC6774301 fatcat:lvmfexm4kfhpnp6zxqjjrjqhou

Predicting Nonspecific Ion Binding Using DelPhi

Marharyta Petukh, Maxim Zhenirovskyy, Chuan Li, Lin Li, Lin Wang, Emil Alexov
2012 Biophysical Journal  
Ions are an important component of the cell and affect the corresponding biological macromolecules either via direct binding or as a screening ion cloud. Although some ion binding is highly specific and frequently associated with the function of the macromolecule, other ions bind to the protein surface nonspecifically, presumably because the electrostatic attraction is strong enough to immobilize them. Here, we test such a scenario and demonstrate that experimentally identified surfacebound
more » ... are located at a potential that facilitates binding, which indicates that the major driving force is the electrostatics. Without taking into consideration geometrical factors and structural fluctuations, we show that ions tend to be bound onto the protein surface at positions with strong potential but with polarity opposite to that of the ion. This observation is used to develop a method that uses a DelPhi-calculated potential map in conjunction with an in-house-developed clustering algorithm to predict nonspecific ion-binding sites. Although this approach distinguishes only the polarity of the ions, and not their chemical nature, it can predict nonspecific binding of positively or negatively charged ions with acceptable accuracy. One can use the predictions in the Poisson-Boltzmann approach by placing explicit ions in the predicted positions, which in turn will reduce the magnitude of the local potential and extend the limits of the Poisson-Boltzmann equation. In addition, one can use this approach to place the desired number of ions before conducting molecular-dynamics simulations to neutralize the net charge of the protein, because it was shown to perform better than standard screened Coulomb canned routines, or to predict ion-binding sites in proteins. This latter is especially true for proteins that are involved in ion transport, because such ions are loosely bound and very difficult to detect experimentally.
doi:10.1016/j.bpj.2012.05.013 pmid:22735539 pmcid:PMC3379622 fatcat:brxgviwt25cyvklpiqtfb4gv6q

Modeling CLIC2-RyR Interactions and the Effect of Disease Causing Mutation

Shawn Witham, Emil Alexov
2012 Biophysical Journal  
Alexov.  ...  train machine learning algorithms to identify which real protein sequences are designable. 2320-Pos Board B90 Modeling CLIC2-RyR Interactions and the Effect of Disease Causing Mutation Shawn Witham, Emil  ...  Alexov.  ... 
doi:10.1016/j.bpj.2011.11.2501 fatcat:fo4zozhidnc57pruulyygkkf7u

Molecular Mechanisms of Disease-Causing Missense Mutations

Shannon Stefl, Hafumi Nishi, Marharyta Petukh, Anna R. Panchenko, Emil Alexov
2013 Journal of Molecular Biology  
Genetic variations resulting in a change of amino acid sequence can have a dramatic effect on stability, hydrogen bond network, conformational dynamics, activity and many other physiologically important properties of proteins. The substitutions of only one residue in a protein sequence, so-called missense mutations, can be related to many pathological conditions, and may influence susceptibility to disease and drug treatment. The plausible effects of missense mutations range from affecting the
more » ... acromolecular stability to perturbing macromolecular interactions and cellular localization. Here we review the individual cases and genome-wide studies which illustrate the association between missense mutations and diseases. In addition we emphasize that the molecular mechanisms of effects of mutations should be revealed in order to understand the disease origin. Finally we report the current state-of-the-art methodologies which predict the effects of mutations on protein stability, the hydrogen bond network, pH-dependence, conformational dynamics and protein function.
doi:10.1016/j.jmb.2013.07.014 pmid:23871686 pmcid:PMC3796015 fatcat:bgnva3rqxrbglcu7tz2lxmi6r4

On the electrostatic properties of homodimeric proteins

Brandon Campbell, Marharyta Petukh, Emil Alexov, Chuan Li
2014 Journal of Theoretical and Computational Chemistry  
A large fraction of proteins function as homodimers, but it is not always clear why the dimerization is important for functionality since frequently each monomer possesses a distinctive active site. Recent work (PLoS Computational Biology, 9(2), e1002924) indicates that homodimerization may be important for forming an electrostatic funnel in the spermine synthase homodimer which guides changed substrates toward the active centers. This prompted us to investigate the electrostatic properties of
more » ... large set of homodimeric proteins and resulted in an observation that in a vast majority of the cases the dimerization indeed results in specific electrostatic features, although not necessarily in an electrostatic funnel. It is demonstrated that the electrostatic dipole moment of the dimer is predominantly perpendicular to the axis connecting the centers of the mass of the monomers. In addition, the surface points with highest potential are located in the proximity of the interfacial plane of the homodimeric complexes. These findings indicate that frequently homodimerization provides specific electrostatic features needed for the function of proteins.
doi:10.1142/s0219633614400070 pmid:25419028 pmcid:PMC4238107 fatcat:o3hw34jtxbbiraxlbtwcaw5jy4

A regularization approach for solving Poisson's equation with singular charge sources and diffuse interfaces [article]

Siwen Wang, Arum Lee, Emil Alexov, Shan Zhao
2019 arXiv   pre-print
Singular charge sources in terms of Dirac delta functions present a well-known numerical challenge for solving Poisson's equation. For a sharp interface between inhomogeneous media, singular charges could be analytically treated by fundamental solutions or regularization methods. However, no analytical treatment is known in the literature in case of a diffuse interface of complex shape. This letter reports the first such regularization method that represents the Coulomb potential component
more » ... tically by Green's functions to account for singular charges. The other component, i.e., the reaction field potential, then satisfies a regularized Poisson equation with a smooth source and the original elliptic operator. The regularized equation can then be simply solved by any numerical method. For a spherical domain with diffuse interface, the proposed regularization method is numerically validated and compared with a semi-analytical quasi-harmonic method.
arXiv:1910.00425v1 fatcat:2wtnnvh7ffc6rcu4vaurgvp7p4

Protonation and pK changes in protein–ligand binding

Alexey V. Onufriev, Emil Alexov
2013 Quarterly Reviews of Biophysics (print)  
Onufriev and Alexov  ...  Onufriev and Alexov Author Manuscript † The charges were manipulated by modifying the charge column in the "marked" file output by "mark sur" program within the ZDOCK distribution.  ...  Alexov Page 33 Table 1 1 Q Rev Biophys.  ... 
doi:10.1017/s0033583513000024 pmid:23889892 pmcid:PMC4437766 fatcat:hvu5ufzt65ds3oe5nqz4swxcxe

Optimization of Electrostatic Interactions in Protein-Protein Complexes

Kelly Brock, Kemper Talley, Kacey Coley, Petras Kundrotas, Emil Alexov
2007 Biophysical Journal  
In this article, we present a statistical analysis of the electrostatic properties of 298 protein-protein complexes and 356 domain-domain structures extracted from the previously developed database of protein complexes (ProtCom, http:// For each structure in the dataset we calculated the total electrostatic energy of the binding and its two components, Coulombic and reaction field energy. It was found that in a vast majority of the cases (.90%), the total
more » ... ectrostatic component of the binding energy was unfavorable. At the same time, the Coulombic component of the binding energy was found to favor the complex formation while the reaction field component of the binding energy opposed the binding. It was also demonstrated that the components in a wild-type (WT) structure are optimized/anti-optimized with respect to the corresponding distributions, arising from random shuffling of the charged side chains. The degree of this optimization was assessed through the Z-score of WT energy in respect to the random distribution. It was found that the Z-scores of Coulombic interactions peak at a considerably negative value for all 654 cases considered while the Z-score of the reaction field energy varied among different types of complexes. All these findings indicate that the Coulombic interactions within WT protein-protein complexes are optimized to favor the complex formation while the total electrostatic energy predominantly opposes the binding. This observation was used to discriminate WT structures among sets of structural decoys and showed that the electrostatic component of the binding energy is not a good discriminator of the WT; while, Coulombic or reaction field energies perform better depending upon the decoy set used.
doi:10.1529/biophysj.107.112367 pmid:17693468 pmcid:PMC2072065 fatcat:62ev62cairholpjgks4iamrs3u
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