Biological and Chemical Physics Commons^™

Between Algorithm And Model: Different Molecular Surface Definitions For The Poisson-Boltzmann Based Electrostatic Characterization Of Biomolecules In Solution, Sergio Decherchi, José Colmenares, Chiara Eva Catalano, Michela Spagnuolo, Emil Alexov, Walter Rocchia

Publications

The definition of a molecular surface which is physically sound and computationally efficient is a very interesting and long standing problem in the implicit solvent continuum modeling of biomolecular systems as well as in the molecular graphics field. In this work, two molecular surfaces are evaluated with respect to their suitability for electrostatic computation as alternatives to the widely used Connolly-Richards surface: the blobby surface, an implicit Gaussian atom centered surface, and the skin surface. As figures of merit, we considered surface differentiability and surface area continuity with respect to atom positions, and the agreement with explicit solvent simulations. Geometric …

Protein Nano-Object Integrator (Pronoi) For Generating Atomic Style Objects For Molecular Modeling, Nicholas Smith, Brandon Campbell, Lin Li, Chuan Li, Emil Alexov

Publications

Background

With the progress of nanotechnology, one frequently has to model biological macromolecules simultaneously with nano-objects. However, the atomic structures of the nano objects are typically not available or they are solid state entities. Because of that, the researchers have to investigate such nano systems by generating models of the nano objects in a manner that the existing software be able to carry the simulations. In addition, it should allow generating composite objects with complex shape by combining basic geometrical figures and embedding biological macromolecules within the system.

Results

Here we report the Protein Nano-Object Integrator (ProNOI) which allows for …

Highly Efficient And Exact Method For Parallelization Of Grid-Based Algorithms And Its Implementation In Delphi, Chuan Li, Lin Li, Jie Zhang, Emil Alexov

Publications

The Gauss–Seidel (GS) method is a standard iterative numerical method widely used to solve a system of equations and, in general, is more efficient comparing to other iterative methods, such as the Jacobi method. However, standard implementation of the GS method restricts its utilization in parallel computing due to its requirement of using updated neighboring values (i.e., in current iteration) as soon as they are available. Here, we report an efficient and exact (not requiring assumptions) method to parallelize iterations and to reduce the computational time as a linear/nearly linear function of the number of processes or computing units. In …

Predicting Nonspecific Ion Binding Using Delphi, Marharyta Petukh, Maxim Zhenirovskyy, Chuan Li, Lin Li, Lin Wang, Emil Alexov

Publications

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 surface-bound ions 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 …

Delphi: A Comprehensive Suite For Delphi Software And Associated Resources, Lin Li, Chuan Li, Subhra Sarkar, Jie Zhang, Shawn Witham, Zhe Zhang, Lin Wang, Nicholas Smith, Marharyta Petukh, Emil Alexov

Publications

Background

Accurate modeling of electrostatic potential and corresponding energies becomes increasingly important for understanding properties of biological macromolecules and their complexes. However, this is not an easy task due to the irregular shape of biological entities and the presence of water and mobile ions.

Results

Here we report a comprehensive suite for the well-known Poisson-Boltzmann solver, DelPhi, enriched with additional features to facilitate DelPhi usage. The suite allows for easy download of both DelPhi executable files and source code along with a makefile for local installations. The users can obtain the DelPhi manual and parameter files required for the corresponding …

Analyzing Effects Of Naturally Occurring Missense Mutations, Zhe Zhang, Maria A. Miteva, Lin Wang, Emil Alexov

Publications

Single-point mutation in genome, for example, single-nucleotide polymorphism (SNP) or rare genetic mutation, is the change of a single nucleotide for another in the genome sequence. Some of them will produce an amino acid substitution in the corresponding protein sequence (missense mutations); others will not. This paper focuses on genetic mutations resulting in a change in the amino acid sequence of the corresponding protein and how to assess their effects on protein wild-type characteristics. The existing methods and approaches for predicting the effects of mutation on protein stability, structure, and dynamics are outlined and discussed with respect to their underlying …

Developing Hybrid Approaches To Predict Pka Values Of Ionizable Groups, Shawn Witham, Kemper Talley, Lin Wang, Zhe Zhang, Daquan Gao, Wei Yang, Emil Alexov

Publications

Accurate predictions of pKa values of titratable groups require taking into account all relevant processes associated with the ionization/deionization. Frequently, however, the ionization does not involve significant structural changes and the dominating effects are purely electrostatic in origin allowing accurate predictions to be made based on the electrostatic energy difference between ionized and neutral forms alone using a static structure. On another hand, if the change of the charge state is accompanied by a structural reorganization of the target protein, then the relevant conformational changes have to be taken into account in the pKa calculations. Here we report a hybrid …

Progress In The Prediction Of Pka Values In Proteins, Emil Alexov, Ernest L. Mehler, Nathan Baker, Antonio Baptista, Yong Huang, Francesca Milletti, Jens Erik Nielsen, Damien Farrell, Tommy Carstensen, Mats H.M. Olsson, Jana K. Shen, Jim Warwicker, Sarah Williams, J Michael Word

Publications

The pK_a-cooperative aims to provide a forum for experimental and theoretical researchers interested in protein pK_a values and protein electrostatics in general. The first round of the pK_a-cooperative, which challenged computational labs to carry out blind predictions against pK_as experimentally determined in the laboratory of Bertrand Garcia-Moreno, was completed and results discussed at the Telluride meeting (July 6–10, 2009). This article serves as an introduction to the reports submitted by the blind prediction participants that will be published in a special issue of PROTEINS: Structure, Function and Bioinformatics. …

A Missense Mutation In Clic2 Associated With Intellectual Disability Is Predicted By In Silico Modeling To Affect Protein Stability And Dynamics, Shawn Witham, Kyoko Takano, Charles Schwartz, Emil Alexov

Publications

Large-scale next generation resequencing of X chromosome genes identified a missense mutation in the CLIC2 gene on Xq28 in a male with X-linked intellectual disability (XLID) and not found in healthy individuals. At the same time, numerous nsSNPs (nonsynonomous SNP) have been reported in the CLIC2 gene in healthy individuals indicating that the CLIC2 protein can tolerate amino acid substitutions and be fully functional. To test the possibility that p.H101Q is a disease-causing mutation, we performed in silico simulations to calculate the effects of the p.H101Q mutation on CLIC2 stability, dynamics, and ionization states while comparing the effects obtained for …

On The Role Of Electrostatics In Protein–Protein Interactions, Zhe Zhang, Shawn Witham, Emil Alexov

Publications

The role of electrostatics in protein–protein interactions and binding is reviewed in this paper. A brief outline of the computational modeling, in the framework of continuum electrostatics, is presented and the basic electrostatic effects occurring upon the formation of the complex are discussed. The effect of the salt concentration and pH of the water phase on protein–protein binding free energy is demonstrated which indicates that the increase of the salt concentration tends to weaken the binding, 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 …

In Silico And In Vitro Investigations Of The Mutability Of Disease-Causing Missense Mutation Sites In Spermine Synthase, Zhe Zhang, Joy Norris, Charles Schwartz, Emil Alexov

Publications

Background

Spermine synthase (SMS) is a key enzyme controlling the concentration of spermidine and spermine in the cell. The importance of SMS is manifested by the fact that single missense mutations were found to cause Snyder-Robinson Syndrome (SRS). At the same time, currently there are no non-synonymous single nucleoside polymorphisms, nsSNPs (harmless mutations), found in SMS, which may imply that the SMS does not tolerate amino acid substitutions, i.e. is not mutable.

Methodology/Principal Findings

To investigate the mutability of the SMS, we carried out in silico analysis and in vitro experiments of the effects of amino acid substitutions at the …

In Silico Modeling Of Ph-Optimum Of Protein-Protein Binding, Rooplekha C. Mitra, Zhe Zhang, Emil Alexov

Publications

Protein-protein association is a pH-dependent process and thus the binding affinity depends on the local pH. In vivo the association occurs in a particular cellular compartment, where the individual monomers are supposed to meet and form a complex. Since the monomers and the complex exist in the same micro environment, it is plausible that they coevolved toward its properties, in particular, toward the characteristic subcellular pH. Here we show that the pH at which the monomers are most stable (pH-optimum) or the pH at which stability is almost pH-independent (pH-flat) of monomers are correlated with the pH-optimum of maximal affinity …

Computational Analysis Of Missense Mutations Causing Snyder-Robinson Syndrome, Zhe Zhang, Shaolei Teng, Liangjiang Wang, Charles E. Schwartz, Emil Alexov

Publications

The Snyder-Robinson syndrome is caused by missense mutations in the spermine sythase gene that encodes a protein (SMS) of 529 amino acids. Here we investigate, in silico, the molecular effect of three missense mutations, c.267G>A (p.G56S), c.496T>G (p.V132G), and c.550T>C (p.I150T) in SMS that were clinically identified to cause the disease. Single-point energy calculations, molecular dynamics simulations, and pKa calculations revealed the effects of these mutations on SMS's stability, flexibility, and interactions. It was predicted that the catalytic residue, Asp276, should be protonated prior binding the substrates. The pKa calculations indicated the p.I150T mutation causes pKa changes …

Understanding The Role Of Electrostatics On Protein-Protein Binding, Rooplekha C Mitra

All Theses

Ionized groups carry net charge and thus play a major role in the electrostatic interactions between the ligand and receptor. So understanding the role of electrostatics on protein-protein interactions is crucial for understanding the contribution of ionizable groups to the binding. However, their ionization states depend on many factors including pH of water phase. The complexity comes from the fact that the pKa's of ionizable groups may be quite different from their standard values and even may change due to protein-protein binding. The main difficulty in modeling plausible ionization changes induced by the complex formation arises from the differences in …

On The Ph-Optimum Of Activity And Stability Of Proteins, Kemper Tally, Emil Alexov

Publications

Biological macromolecules evolved to perform their function in specific cellular environment (subcellular compartments or tissues); therefore, they should be adapted to the biophysical characteristics of the corresponding environment, one of them being the characteristic pH. Many macromolecular properties are pH dependent, such as activity and stability. However, only activity is biologically important, while stability may not be crucial for the corresponding reaction. Here, we show that the pH-optimum of activity (the pH of maximal activity) is correlated with the pH-optimum of stability (the pH of maximal stability) on a set of 310 proteins with available experimental data. We speculate that …

Understanding The Biological And Environmental Implications Of Nanomaterials, Sijie Lin

All Dissertations

The last two decades have witnessed the discovery, development, and large-scale manufacturing of novel nanomaterials. While nanomaterials bring in exciting and extraordinary properties in all areas of materials, electronics, mechanics, and medicine, they also could generate potential adverse effects in biological systems and in the environment. The currently limited application of nanomaterials in biological and ecological systems results from the insufficient and often controversial data on describing the complex behaviors of nanomaterials in living systems. The purpose of this dissertation intends to fill such a knowledge void with methodologies from the disciplines of biophysics, biology, and materials science and engineering. …

Structural Assessment Of The Effects Of Amino Acid Substitutions On Protein Stability And Protein-Protein Interaction, Shaolei Teng, Liangjiang Wang, Anand K. Srivastava, Charles E. Schwartz, Emil Alexov

Publications

A structure-based approach is described for predicting the effects of amino acid substitutions on protein function. Structures were predicted using a homology modelling method. Folding and binding energy differences between wild-type and mutant structures were computed to quantitatively assess the effects of amino acid substitutions on protein stability and protein–protein interaction, respectively. We demonstrated that pathogenic mutations at the interaction interface could affect binding energy and destabilise protein complex, whereas mutations at the non-interface might reduce folding energy and destabilise monomer structure. The results suggest that the structure-based analysis can provide useful information for understanding the molecular mechanisms of diseases.

Modeling Effects Of Human Single Nucleotide Polymorphisms On Protein-Protein Interactions, Shaolei Teng, Thomas Madej, Anna Panchenko, Emil Alexov

Publications

A large set of three-dimensional structures of 264 protein-protein complexes with known nonsynonymous single nucleotide polymorphisms (nsSNPs) at the interface was built using homology-based methods. The nsSNPs were mapped on the proteins' structures and their effect on the binding energy was investigated with CHARMM force field and continuum electrostatic calculations. Two sets of nsSNPs were studied: disease annotated Online Mendelian Inheritance in Man (OMIM) and nonannotated (non-OMIM). It was demonstrated that OMIM nsSNPs tend to destabilize the electrostatic component of the binding energy, in contrast with the effect of non-OMIM nsSNPs. In addition, it was shown that the change of …

Optimization Of Electrostatic Interactions In Protein-Protein Complexes, Kelly Brock, Kemper Talley, Kacey Coley, Petras Kundrotas, Emil Alexov

Publications

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://www.ces.clemson.edu/compbio/protcom). 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 electrostatic 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 …

Carbon Nanomaterials In Biological Systems, Sijie Lin

All Theses

ABSTRACT


This thesis intends to present, from the biophysical viewpoint, my study on understanding carbon nanomaterials in biological and environmental systems. Carbon nanotubes and fullerenes represent a major family of carbon nanoparticles which possess distinct electrical, optical and mechanical properties. However, the major hurdle for making carbon nanomaterials bioavailable lies in their tendency toward bundling, driven by hydrophobic interaction, van der Waals force, and pi-stacking. To overcome this problem, we used non-covalent binding of zwitterionic lysophopholipids (LPL) onto the external surfaces of single-walled carbon nanotubes (SWNTs). This method affords superior SWNT solubility in aqueous solution. The stability of SWNT-LPL complex …

Poisson-Boltzmann Calculations Of Nonspecific Salt Effects On Protein-Protein Binding Free Energies, Claudia Bertonati, Barry Honig, Emil Alexov

Publications

The salt dependence of the binding free energy of five protein-protein hetero-dimers and two homo-dimers/tetramers was calculated from numerical solutions to the Poisson-Boltzmann equation. Overall, the agreement with experimental values is very good. In all cases except one involving the highly charged lactoglobulin homo-dimer, increasing the salt concentration is found both experimentally and theoretically to decrease the binding affinity. To clarify the source of salt effects, the salt-dependent free energy of binding is partitioned into screening terms and to self-energy terms that involve the interaction of the charge distribution of a monomer with its own ion atmosphere. In six of …

Predicting Residue Contacts Using Pragmatic Correlated Mutations Method: Reducing The False Positives, Petras J. Kundrotas, Emil Alexov

Publications

Background

Predicting residues' contacts using primary amino acid sequence alone is an important task that can guide 3D structure modeling and can verify the quality of the predicted 3D structures. The correlated mutations (CM) method serves as the most promising approach and it has been used to predict amino acids pairs that are distant in the primary sequence but form contacts in the native 3D structure of homologous proteins.

Results

Here we report a new implementation of the CM method with an added set of selection rules (filters). The parameters of the algorithm were optimized against fifteen high resolution crystal …

Protcom: Searchable Database Of Protein Complexes Enhanced With Domain-Domain Structures, Petras Kundrotas, Emil Alexov

Publications

The database of protein complexes (PROTCOM) is a compilation of known 3D structures of protein–protein complexes enriched with artificially created domain–domain structures using the available entries in the Protein Data Bank. The domain–domain structures are generated by parsing single chain structures into loosely connected domains and are important features of the database. The database (http://www.ces.clemson.edu/compbio/protcom) could be used for benchmarking purposes of the docking and other algorithms for predicting 3D structures of protein–protein complexes. The database can be utilized as a template database in the homology or threading methods for modeling the 3D structures of unknown protein–protein complexes. …

Electrostatic Properties Of Protein-Protein Complexes, Petras J. Kundrotas, Emil Alexov

Publications

Statistical electrostatic analysis of 37 protein-protein complexes extracted from the previously developed database of protein complexes (ProtCom, http://www.ces.clemson.edu/compbio/protcom) is presented. It is shown that small interfaces have a higher content of charged and polar groups compared to large interfaces. In a vast majority of the cases the average pK_a shifts for acidic residues induced by the complex formation are negative, indicating that complex formation stabilizes their ionizable states, whereas the histidines are predicted to destabilize the complex. The individual pK_a shifts show the same tendency since 80% of the interfacial acidic groups were found to lower their …