Emil Alexov | Clemson University (original) (raw)

Papers by Emil Alexov

<p>The vertical axis of the graph shows activity normalized to 100% for the G56S SMS mutant... more <p>The vertical axis of the graph shows activity normalized to 100% for the G56S SMS mutant without the binding of small molecules. The horizontal axis indicates the small molecule ID number. The newly tested here 51 molecules are shown in grey and the previously tested 10 molecules <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0110884#pone.0110884-Zhang6" target="_blank">[51]</a> are shown in black.</p

International Journal of Molecular Sciences

The development of methods and algorithms to predict the effect of mutations on protein stability... more The development of methods and algorithms to predict the effect of mutations on protein stability, protein–protein interaction, and protein–DNA/RNA binding is necessitated by the needs of protein engineering and for understanding the molecular mechanism of disease-causing variants. The vast majority of the leading methods require a database of experimentally measured folding and binding free energy changes for training. These databases are collections of experimental data taken from scientific investigations typically aimed at probing the role of particular residues on the above-mentioned thermodynamic characteristics, i.e., the mutations are not introduced at random and do not necessarily represent mutations originating from single nucleotide variants (SNV). Thus, the reported performance of the leading algorithms assessed on these databases or other limited cases may not be applicable for predicting the effect of SNVs seen in the human population. Indeed, we demonstrate that the S...

Bulletin of the American Physical Society, 2006

Submitted for the MAR06 Meeting of The American Physical Society Combining biophysical and bioinf... more Submitted for the MAR06 Meeting of The American Physical Society Combining biophysical and bioinformatical approaches for predicting residue's contacts. EMIL ALEXOV, AMBER ALLARDICE, PETRAS KUNDROTAS, Clemson University-One of the most important task of the post genomics era is to utilize the enormous sequence information delivered from the genomes and to predict 3D structure of proteins. The quality of the predicted structure depends on many factors including the improvement made in ab initio, threading and homology modeling methods. Here we combine the method of correlated mutations with biophysical restrains in order to predict residue's contacts from amino acids sequence alone. The parameters of the protocol were optimized against a set of 21 proteins with known high resolution 3D structures. The effects of the degree of residue conservation, sequence similarity among the sequences within the multiple sequence alignment and conservation coefficient of two amino acids positions were studied. It was shown that the prediction accuracy of the method of correlated mutations alone is pure, on average only 10% of the contacts are predicted correctly. However, adding biophysical filters greatly improves the accuracy of the predictions. Thus, implying pairing rules for charged, polar and hydrophobic residues significantly reduces the total number of the predictions, e.g. reduces the coverage, however, most of the rejected predictions are false positives. As result, the relative rate of the correct predictions increases.

Genes, 2020

Single-nucleotide variants (SNVs) are a major form of genetic variation in the human genome that ... more 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 developed 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 featu...

Plasma Physics and Controlled Fusion, 1990

ABSTRACT

Biophysical Chemistry, 1996

Database, 2018

Supplement Overview • An Overview of Web Services: A summary of the web applications that handle ... more Supplement Overview • An Overview of Web Services: A summary of the web applications that handle biological networks. • BEL Commons Implementation Details: Technical details about the architecture and the technologies used to implement BEL Commons. • Tutorial: References to the tutorial that outlines the Application Scenario presented in this paper. • References : References used in this document An Overview of Web Applications Here, we present a brief overview on some of the web applications mentioned in the introduction of the manuscript (Supplementary Table 1). We also present a comparison of features (Supplementary Table 2) and visualization techniques (Supplementary Table 3) implemented by these applications. Platform Focus Export Visualization WikiPathways (Pico et al ., 2008) Crowdsourcing biological model building SBML PathVisio, Cytoscape Pathway Commons (Cerami et al ., 2010) Aggregating pathway databases BioPax, SMBL, SIF, etc. BioPAX CyPath2, PaxToolsR, ChiBE NDEx (Pratt et al ., 2015) General network storage from CX CX Cytoscape.js GraphSpace (Braradwaj et al ., 2017) General network storage from Cytoscape Cytoscape JSON Cytoscape.js SBV Improver (Meyer et al ., 2015) Verification of semi-automated relation extraction results SIF, JGIF Custom Viewer Causal Biological Networks Database (Boué et al ., 2015)

ACS Omega, 2022

Here, we present a Gaussian-based method for estimation of protein−protein binding entropy to aug... more Here, we present a Gaussian-based method for estimation of protein−protein binding entropy to augment the molecular mechanics Poisson−Boltzmann surface area (MM/PBSA) method for computational prediction of binding free energy (ΔG). The method is termed f5-MM/PBSA/E, where "E" stands for entropy and f5 for five adjustable parameters. The enthalpy components of ΔG (molecular mechanics, polar and non-polar solvation energies) are computed from a single implicit solvent generalized Born (GB) energy minimized structure of a protein−protein complex, while the binding entropy is computed using independently GB energy minimized unbound and bound structures. It should be emphasized that the f5-MM/PBSA/E method does not use snapshots, just energy minimized structures, and is thus very fast and computationally efficient. The method is trained and benchmarked in 5-fold validation test over a data set consisting of 46 protein−protein binding cases with experimentally determined dissociation constant K d values. This data set has been used for benchmarking in recently published protein−protein binding studies that apply conventional MM/PBSA and MM/PBSA with an enhanced sampling method. The f5-MM/PBSA/E tested on the same data set achieves similar or better performance than these computationally demanding approaches, making it an excellent choice for high throughput protein−protein binding affinity prediction studies.

Abstract: DNA mutations are the cause of many human diseases and they are the reason for natural ... more Abstract: DNA mutations are the cause of many human diseases and they are the reason for natural differences among individuals by affecting the structure, function, interactions, and other properties of DNA and expressed proteins. The ability to predict whether a given mutation is disease-causing or harmless is of great importance for the early detection of patients with a high risk of developing a particular disease and would pave the way for personalized medicine and diagnostics. Here we review existing methods and techniques to study and predict the effects of DNA mutations from three different perspectives: in silico, in vitro and in vivo. It is emphasized that the problem is complicated and successful detection of a pathogenic mutation frequently requires a combination of several methods and a knowledge of the biological phenomena associated with the corresponding macromolecules.

International Journal of Molecular Sciences, 2020

Ions play significant roles in biological processes—they may specifically bind to a protein site ... more Ions play significant roles in biological processes—they may specifically bind to a protein site or bind non-specifically on its surface. Although the role of specifically bound ions ranges from actively providing structural compactness via coordination of charge–charge interactions to numerous enzymatic activities, non-specifically surface-bound ions are also crucial to maintaining a protein’s stability, responding to pH and ion concentration changes, and contributing to other biological processes. However, the experimental determination of the positions of non-specifically bound ions is not trivial, since they may have a low residential time and experience significant thermal fluctuation of their positions. Here, we report a new release of a computational method, the BION-2 method, that predicts the positions of non-specifically surface-bound ions. The BION-2 utilizes the Gaussian-based treatment of ions within the framework of the modified Poisson–Boltzmann equation, which does n...

Background: Ions play significant roles in biological processes - they may specifically bind to a... more Background: Ions play significant roles in biological processes - they may specifically bind to a protein site or bind non-specifically on its surface. Though, the role of specifically bound ions range from actively providing structural compactness via coordination of charge-charge interactions to numerous enzymatic activities, non-specifically surface-bound ions are also crucial to maintaining a protein’s stability, responding to pH and ion concentration changes and contributing to other biological processes. However, experimental determination of positions of non-specifically bound ions is not trivial since they may have low residential time and experience significant thermal fluctuation of their positions. Results: Here we report a new release of a computational method, the BION-2 method, that predicts positions of non-specifically surface-bound ions. The BION-2 utilizes the Gaussian-based treatment of ions within the framework of the modified Poisson-Boltzmann equation, that doe...

Scientific reports, Jan 5, 2018

Macromolecular binding is a complex process that involves sensing and approaching the binding par... more Macromolecular binding is a complex process that involves sensing and approaching the binding partner, adopting the proper orientation, and performing the physical binding. We computationally investigated the role of E-hooks, which are intrinsically disordered regions (IDRs) at the C-terminus of tubulin, on dynein microtubule binding domain (MTBD) binding to the microtubule as a function of the distance between the MTBD and its binding site on the microtubule. Our results demonstrated that the contacts between E-hooks and the MTBD are dynamical; multiple negatively charted patches of amino acids on the E-hooks grab and release the same positively charged patches on the MTBD as it approaches the microtubule. Even when the distance between the MTBD and the microtubule was greater than the E-hook length, the E-hooks sensed and guided MTBD via long-range electrostatic interactions in our simulations. Moreover, we found that E-hooks exerted electrostatic forces on the MTBD that were dist...

Scientific reports, Jan 15, 2017

The ability to predict if a given mutation is disease-causing or not has enormous potential to im... more The ability to predict if a given mutation is disease-causing or not has enormous potential to impact human health. Typically, these predictions are made by assessing the effects of mutation on macromolecular stability and amino acid conservation. Here we report a novel feature: the electrostatic component of the force acting between a kinesin motor domain and tubulin. We demonstrate that changes in the electrostatic component of the binding force are able to discriminate between disease-causing and non-disease-causing mutations found in human kinesin motor domains using the receiver operating characteristic (ROC). Because diseases may originate from multiple effects not related to kinesin-microtubule binding, the prediction rate of 0.843 area under the ROC plot due to the change in magnitude of the electrostatic force alone is remarkable. These results reflect the dependence of kinesin's function on motility along the microtubule, which suggests a precise balance of microtubule...

Journal of computational chemistry, Jan 11, 2017

The standard treatment of ions in the framework of the Poisson-Boltzmann equation relies on molec... more The standard treatment of ions in the framework of the Poisson-Boltzmann equation relies on molecular surfaces, which are commonly constructed along with the Stern layer. The molecular surface determines where ions can be present. In the Gaussian-based smooth dielectric function in DelPhi, smooth boundaries between the solute and solvent take the place of molecular surface. Therefore, this invokes the question of how to model mobile ions in the water phase without a definite solute-solvent boundary. This article reports a natural extension of the Gaussian-based smooth dielectric function approach that treats mobile ions via Boltzmann distribution with an added desolvation penalty. Thus, ion concentration near macromolecules is governed by the local electrostatic potential and the desolvation penalty (from being partially desolvated). The approach is tested against the experimental salt dependence of binding free energy on 7 protein-protein complexes and 12 DNA-protein complexes, res...

Biochemistry, Apr 20, 2017

Ca2+-Calmodulin-dependent protein kinase II (CaMKII) is highly abundant in neurons, where its con... more Ca2+-Calmodulin-dependent protein kinase II (CaMKII) is highly abundant in neurons, where its concentration reaches that typically found for cytoskeletal proteins. Functional reasons for such a high concentration are not known, but given the multitude of known binding partners for CaMKII, a role as a scaffolding molecule has been proposed. In this report, we provide experimental evidence that demonstrates a novel structural role for CaMKII. We discovered that CaMKII forms filaments that can extend for several microns in the presence of certain divalent cations (Zn2+, Cd2+ and Cu2+) but not with others (Ca2+, Mg2+, Co2+ and Ni2+). Once formed, depleting the divalent ion concentration with chelators completely dissociated the filaments and this process could be repeated by cyclic addition and removal of divalent ions. Using the crystal structure of the CaMKII holoenzyme, we computed an electrostatic potential map of the dodecameric complex to predict divalent ion binding sites. This a...

Proteins: Structure, Function, and Bioinformatics, 2016

The KDM5C gene (also known as JARID1C and SMCX) is located on the X chromosome and encodes a ubiq... more The KDM5C gene (also known as JARID1C and SMCX) is located on the X chromosome and encodes a ubiquitously expressed 1,560-aa protein, which plays an important role in lysine methylation (specifically reverses tri-and di-methylation of Lys4 of histone H3). Currently, thirteen missense mutations in KDM5C have been linked to X-linked mental retardation. However, the molecular mechanism of disease is currently unknown due to the experimental difficulties in expressing such large protein and the lack of experimental 3D structure. In this work, we utilize homology modeling, docking, and experimental data to predict 3D structures of KDM5C domains and their mutual arrangement. The resulting quaternary structure includes KDM5C JmjN, ARID, PHD1, JmjC, ZF domains, substrate histone peptide, enzymatic cofactors and DNA. The predicted quaternary structure was investigated with molecular dynamic simulation for its stability, and further analysis was carried out to identify features measured experimentally. The predicted structure of KDM5C was used to investigate the effects of disease-causing mutations and it was shown that the mutations alter domain stability and inter-domain interactions. The structural model reported in this work could prompt experimental investigations of KDM5C domain-domain interaction and exploration of undiscovered functionalities.

Journal of computational chemistry, Jan 21, 2016

Macromolecular interactions are essential for understanding numerous biological processes and are... more Macromolecular interactions are essential for understanding numerous biological processes and are typically characterized by the binding free energy. Important component of the binding free energy is the electrostatics, which is frequently modeled via the solutions of the Poisson-Boltzmann Equations (PBE). However, numerous works have shown that the electrostatic component (ΔΔGelec ) of binding free energy is very sensitive to the parameters used and modeling protocol. This prompted some researchers to question the robustness of PBE in predicting ΔΔGelec . We argue that the sensitivity of the absolute ΔΔGelec calculated with PBE using different input parameters and definitions does not indicate PBE deficiency, rather this is what should be expected. We show how the apparent sensitivity should be interpreted in terms of the underlying changes in several numerous and physical parameters. We demonstrate that PBE approach is robust within each considered force field (CHARMM-27, AMBER-94...

International Journal of Molecular Sciences, 2015

Mutations in KDM5C gene are linked to X-linked mental retardation, the syndromic Claes-Jensen-typ... more Mutations in KDM5C gene are linked to X-linked mental retardation, the syndromic Claes-Jensen-type disease. This study focuses on non-synonymous mutations in the KDM5C ARID domain and evaluates the effects of two disease-associated missense mutations (A77T and D87G) and three not-yet-classified missense mutations (R108W, N142S, and R179H). We predict the ARID domain's folding and binding free energy changes due to mutations, and also study the effects of mutations on protein dynamics. Our computational results indicate that A77T and D87G mutants have minimal effect on the KDM5C ARID domain stability and DNA binding. In parallel, the change in the free energy unfolding caused by the mutants A77T and D87G were experimentally measured by urea-induced unfolding experiments and were shown to be similar to the in silico predictions. The evolutionary conservation analysis shows that the disease-associated mutations are located in a highly-conserved part of the ARID structure (N-terminal domain), indicating their importance for the KDM5C function. N-terminal residues' high conservation suggests that either the ARID domain utilizes the N-terminal to interact with other KDM5C domains or the N-terminal is involved in some yet unknown function. The analysis indicates that, among the non-classified mutations, R108W is possibly a disease-associated mutation, while N142S and R179H are probably harmless.

Computational and Mathematical Methods in Medicine, 2015

Rett Syndrome (RTT) is a progressive neurodevelopmental disease affecting females. RTT is caused ... more Rett Syndrome (RTT) is a progressive neurodevelopmental disease affecting females. RTT is caused by mutations in theMECP2gene and various amino acid substitutions have been identified clinically in different domains of the multifunctional MeCP2 protein encoded by this gene. The R133C variant in the methylated-CpG-binding domain (MBD) of MeCP2 is the second most common disease-causing mutation in the MBD. Comparative molecular dynamics simulations of R133C mutant and wild-type MBD have been performed to understand the impact of the mutation on structure, dynamics, and interactions of the protein and subsequently understand the disease mechanism. Two salt bridges within the protein and two critical hydrogen bonds between the protein and DNA are lost upon the R133C mutation. The mutation was found to weaken the interaction with DNA and also cause loss of helicity within the 141-144 region. The structural, dynamical, and energetical consequences of R133C mutation were investigated in de...