Physics Commons^™

Identifying Weak Interdomain Interactions That Stabilize The Supertertiary Structure Of The N-Terminal Tandem Pdz Domains Of Psd-95, Inna S. Yanez Orozco, Frank A. Mindlin, Junyan Ma, Bo Wang, Brie Levesque, Matheu Spencer, Soheila Rezaei Adariani, George Hamilton, Feng Ding, Mark E. Bowen, Hugo Sanabria

Publications

Previous studies of the N-terminal PDZ tandem from PSD-95 produced divergent models and failed to identify interdomain contacts stabilizing the structure. We used ensemble and single-molecule FRET along with replica-exchange molecular dynamics to fully characterize the energy landscape. Simulations and experiments identified two conformations: an open-like conformation with a small contact interface stabilized by salt bridges, and a closed-like conformation with a larger contact interface stabilized by surface-exposed hydrophobic residues. Both interfaces were confirmed experimentally. Proximity of interdomain contacts to the binding pockets may explain the observed coupling between conformation and binding. The low-energy barrier between conformations allows submillisecond dynamics, …

Variations In Biocorona Formation Related To Defects In The Structure Of Single Walled Carbon Nanotubes And The Hyperlipidemic Disease State, Achyut J. Raghavendra, Kristofer Fritz, Sherleen Fu, Jared M. Brown, Ramakrishna Podila, Jonathan H. Shannahan

Publications

Ball-milling utilizes mechanical stress to modify properties of carbon nanotubes (CNTs) including size, capping, and functionalization. Ball-milling, however, may introduce structural defects resulting in altered CNT-biomolecule interactions. Nanomaterial-biomolecule interactions result in the formation of the biocorona (BC), which alters nanomaterial properties, function, and biological responses. The formation of the BC is governed by the nanomaterial physicochemical properties and the physiological environment. Underlying disease states such as cardiovascular disease can alter the biological milieu possibly leading to unique BC identities. In this ex vivo study, we evaluated variations in the formation of the BC on single-walled CNTs (SWCNTs) due to physicochemical …

Contribution Of Engineered Nanomaterials Physicochemical Properties To Mast Cell Degranulation, Monica M. Johnson, Ryan Mendoza, Achyut J. Raghavendra, Ramakrishna Podila, Jared M. Brown

Publications

The rapid development of engineered nanomaterials (ENMs) has grown dramatically in the last decade, with increased use in consumer products, industrial materials, and nanomedicines. However, due to increased manufacturing, there is concern that human and environmental exposures may lead to adverse immune outcomes. Mast cells, central to the innate immune response, are one of the earliest sensors of environmental insult and have been shown to play a role in ENM-mediated immune responses. Our laboratory previously determined that mast cells are activated via a non-FcεRI mediated response following silver nanoparticle (Ag NP) exposure, which was dependent upon key physicochemical properties. Using …

Charge-Transfer Interactions Induce Surface Dependent Conformational Changes In Apolipoprotein Biocorona, Achyut J. Raghavendra, Nasser Alsaleh, Jared M. Brown, Ramakrishna Podila

Publications

Upon introduction into a biological system, engineered nanomaterials (ENMs) rapidly associate with a variety of biomolecules such as proteins and lipids to form a biocorona. The presence of “biocorona” influences nano–bio interactions considerably, and could ultimately result in altered biological responses. Apolipoprotein A-I (ApoA-I), the major constituent of high-density lipoprotein (HDL), is one of the most prevalent proteins found in ENM-biocorona irrespective of ENM nature, size, and shape. Given the importance of ApoA-I in HDL and cholesterol transport, it is necessary to understand the mechanisms of ApoA-I adsorption and the associated structural changes for assessing consequences of ENM exposure. Here, …

Ion Transport Through Macrocapillaries – Oscillations Due To Charge Patch Formation, Dhruva Kulkarni, L.A.M. Lyle, Chad E. Sosolik

Publications

We present results on ion transport through large bore capillaries (macrocapillaries) that probe both the geometric and ion-guided aspects of this ion delivery mechanism. We have demonstrated that guiding in macrocapillaries exhibits position- and angle-dependent transmission properties which are directly related to the capillary material (either metal or insulator) and geometry. Specifically, we have passed 1 keV Rb⁺ ions through glass and metal macrocapillaries, and have observed oscillations for the transmitted ion current passing through the insulating capillaries. Straightforward calculations show that these oscillations can be attributed to beam deflections from charge patches that form on the interior walls …

Rational Design Of Small-Molecule Stabilizers Of Spermine Synthase Dimer By Virtual Screening And Free Energy-Based Approach, Zhe Zhang, Virginie Martiny, David Lagorce, Yoshihiko Ikeguchi, Emil Alexov, Maria A. Miteva

Publications

Snyder-Robinson Syndrome (SRS) is a rare mental retardation disorder which is caused by the malfunctioning of an enzyme, the spermine synthase (SMS), which functions as a homo-dimer. The malfunctioning of SMS in SRS patients is associated with several identified missense mutations that occur away from the active site. This investigation deals with a particular SRS-causing mutation, the G56S mutation, which was shown computationally and experimentally to destabilize the SMS homo-dimer and thus to abolish SMS enzymatic activity. As a proof-of-concept, we explore the possibility to restore the enzymatic activity of the malfunctioning SMS mutant G56S by stabilizing the dimer through …

Problm Web Server: Protein And Membrane Placement And Orientation Package, Taylor Kimmett, Nicholas Smith, Shawn Witham, Marharyta Petukh, Subhra Sarkar, Emil Alexov

Publications

The 3D structures of membrane proteins are typically determined without the presence of a lipid bilayer. For the purpose of studying the role of membranes on the wild type characteristics of the corresponding protein, determining the position and orientation of transmembrane proteins within a membrane environment is highly desirable. Here we report a geometry-based approach to automatically insert a membrane protein with a known 3D structure into pregenerated lipid bilayer membranes with various dimensions and lipid compositions or into a pseudomembrane. The pseudomembrane is built using the Protein Nano-Object Integrator which generates a parallelepiped of user-specified dimensions made up of …

Computational And Experimental Approaches To Reveal The Effects Of Single Nucleotide Polymorphisms With Respect To Disease Diagnostics, Tugba G. Kucukkal, Ye Yang, Susan C. Chapman, Weiguo Cao, Emil Alexov

Publications

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 …

Chronic Beryllium Disease: Revealing The Role Of Beryllium Ion And Small Peptides Binding To Hla-Dp2, Marharyta Petukh, Bohua Wu, Shannon Stefl, Nick Smith, David Hyde-Volpe, Li Wang, Emil Alexov

Publications

Chronic Beryllium (Be) Disease (CBD) is a granulomatous disorder that predominantly affects the lung. The CBD is caused by Be exposure of individuals carrying the HLA-DP2 protein of the major histocompatibility complex class II (MHCII). While the involvement of Be in the development of CBD is obvious and the binding site and the sequence of Be and peptide binding were recently experimentally revealed [1], the interplay between induced conformational changes and the changes of the peptide binding affinity in presence of Be were not investigated. Here we carry out in silico modeling and predict the Be binding to be within …

On The Modeling Of Polar Component Of Solvation Energy Using Smooth Gaussian-Based Dielectric Function, Lin Li, Chuan Li, Emil Alexov

Publications

Traditional implicit methods for modeling electrostatics in biomolecules use a two-dielectric approach: a biomolecule is assigned low dielectric constant while the water phase is considered as a high dielectric constant medium. However, such an approach treats the biomolecule-water interface as a sharp dielectric border between two homogeneous dielectric media and does not account for inhomogeneous dielectric properties of the macromolecule as well. Recently we reported a new development, a smooth Gaussian-based dielectric function which treats the entire system, the solute and the water phase, as inhomogeneous dielectric medium (J Chem Theory Comput. 2013 Apr 9; 9(4): 2126-2136.). Here we examine …

On The Electrostatic Properties Of Homodimeric Proteins, Brandon Campbell, Marharyta Petukh, Emil Alexov, Chuan Li

Publications

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 a 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 …

A Novel P.Leu(381)Phe Mutation In Presenilin 1 Is Associated With Very Early Onset And Unusually Fast Progressing Dementia As Well As Lysosomal Inclusions Typically Seen In Kufs Disease, Natalia Dolzhanskaya, Michael A. Gonzalez, Fiorella Sperziani, Shannon Stefl, Jeffrey Messing, Guang Y. Wen, Emil Alexov, S Stephan Zuchner, Milen Velinov

Publications

Whole exome sequencing in a family with suspected dominant Kufs disease identified a novel Presenilin 1 mutation p.Leu(381)Phe in three brothers who, along with their father, developed progressive dementia and motor deficits in their early 30s. All affected relatives had unusually rapid disease progression (on average 3.6 years from disease onset to death). In silico analysis of mutation p.Leu(381)Phe predicted more detrimental effects when compared to the common Presenilin 1 mutation p.Glu(280)Ala. Electron microscopy study of peripheral fibroblast cells of the proband showed lysosomal inclusions typical for Kufs disease. However his brain autopsy demonstrated typical changes of Alzheimer disease.

Preferential Scattering By Interfacial Charged Defects For Enhanced Thermoelectric Performance In Few-Layered N-Type Bi2te3, Pooja Puneet, Ramakrishna Podila, Mehmet Karakaya, Song Zhu, Jian He, Terry M. Tritt, Mildred S. Dresselhaus, Apparao Rao

Publications

Over the past two decades several nano-structuring methods have helped improve the figure of merit (ZT) in the state-of-the art bulk thermoelectric materials. While these methods could enhance the thermoelectric performance of p-type Bi₂Te₃, it was frustrating to researchers that they proved ineffective for n-type Bi₂Te₃ due to the inevitable deterioration of its thermoelectric properties in the basal plane. Here, we describe a novel chemical-exfoliation spark-plasma-sintering (CE-SPS) nano-structuring process, which transforms the microstructure of n-type Bi₂Te₃ in an extraordinary manner without compromising its basal plane …

Molecular Mechanisms Of Disease-Causing Missense Mutations, Shannon Stefl, Hafumi Nishi, Marharyta Petukh, Anna R. Panchenko, Emil Alexov

Publications

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 macromolecular 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 …

Continuous Development Of Schemes For Parallel Computing Of The Electrostatics In Biological Systems: Implementation In Delphi, Chuan Li, Marharyta Petukh, Lin Li, Emil Alexov

Publications

Due to the enormous importance of electrostatics in molecular biology, calculating the electrostatic potential and corresponding energies has become a standard computational approach for the study of biomolecules and nano-objects immersed in water and salt phase or other media. However, the electrostatics of large macromolecules and macromolecular complexes, including nano-objects, may not be obtainable via explicit methods and even the standard continuum electrostatics methods may not be applicable due to high computational time and memory requirements. Here, we report further development of the parallelization scheme reported in our previous work (J Comput Chem. 2012 Sep 15; 33(24):1960–6.) to include parallelization …

Cancer Missense Mutations Alter Binding Properties Of Proteins And Their Interaction Networks, Hafumi Nisha, Manoj Tyagi, Shaolei Teng, Benjamin A. Shoemaker, Kosuke Hashimoto, Emil Alexov, Stefan Wuchty, Anna R. Panchenko

Publications

Many studies have shown that missense mutations might play an important role in carcinogenesis. However, the extent to which cancer mutations might affect biomolecular interactions remains unclear. Here, we map glioblastoma missense mutations on the human protein interactome, model the structures of affected protein complexes and decipher the effect of mutations on protein-protein, protein-nucleic acid and protein-ion binding interfaces. Although some missense mutations over-stabilize protein complexes, we found that the overall effect of mutations is destabilizing, mostly affecting the electrostatic component of binding energy. We also showed that mutations on interfaces resulted in more drastic changes of amino acid physico-chemical …

The Role Of Protonation States In Ligand-Receptor Recognition And Binding, Marharyta Petukh, Shannon Stefl, Emil Alexov

Publications

In this review we discuss the role of protonation states in receptor-ligand interactions, providing experimental evidences and computational predictions that complex formation may involve titratable groups with unusual pKa’s and that protonation states frequently change from unbound to bound states. These protonation changes result in proton uptake/release, which in turn causes the pHdependence of the binding. Indeed, experimental data strongly suggest that almost any binding is pH-dependent and to be correctly modeled, the protonation states must be properly assigned prior to and after the binding. One may accurately predict the protonation states when provided with the structures of the unbound …

Nanobiotechnology Can Boost Crop Production And Quality: First Evidence From Increased Plant Biomass, Fruit Yield And Phytomedicine Content In Bitter Melon (Momordica Charantia), Chittaranjan Kole, Phullara Kole, K Manoj Randunu, Poonam Choudhary, Ramakrishna Podila, Pu Chen Ke, Apparao M. Rao, Richard K. Marcus

Publications

BACKGROUND:

Recent research on nanoparticles in a number of crops has evidenced for enhanced germination and seedling growth, physiological activities including photosynthetic activity and nitrogen metabolism, mRNA expression and protein level, and also positive changes in gene expression indicating their potential use in crop improvement. We used a medicinally rich vegetable crop, bitter melon, as a model to evaluate the effects of seed treatment with a carbon-based nanoparticle, fullerol [C60(OH)20], on yield of plant biomass and fruit characters, and phytomedicine contents in fruits.

RESULTS:

We confirmed the uptake, translocation and accumulation of fullerol through bright field imaging and Fourier transform …

Progress In Developing Poisson-Boltzmann Equation Solvers, Chuan Li, Marharyta Petukh, Emil Alexov

Publications

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 provided 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 …

A Rational Free Energy-Based Approach To Understanding And Targeting Disease-Causing Missense Mutations., Zhe Zhang, Shawn Witham, Marharita Petukh, Gautier Moroy, Maria Miteva, Yoshihiko Ikeguchi, Emil Alexov

Publications

BACKGROUND AND SIGNIFICANCE:

Intellectual disability is a condition characterized by significant limitations in cognitive abilities and social/behavioral adaptive skills and is an important reason for pediatric, neurologic, and genetic referrals. Approximately 10% of protein-encoding genes on the X chromosome are implicated in intellectual disability, and the corresponding intellectual disability is termed X-linked ID (XLID). Although few mutations and a small number of families have been identified and XLID is rare, collectively the impact of XLID is significant because patients usually are unable to fully participate in society.

OBJECTIVE:

To reveal the molecular mechanisms of various intellectual disabilities and to suggest …

Enhancing Human Spermine Synthase Activity By Engineered Mutations, Zhe Zhang, Yueli Zheng, Margo Petukh, Anthony Pegg, Yoshihiko Ikeguchi, Emil Alexov

Publications

Spermine synthase (SMS) is an enzyme which function is to convert spermidine into spermine. It was shown that gene defects resulting in amino acid changes of the wild type SMS cause Snyder-Robinson syndrome, which is a mild-to-moderate mental disability associated with osteoporosis, facial asymmetry, thin habitus, hypotonia, and a nonspecific movement disorder. These disease-causing missense mutations were demonstrated, both in silico and in vitro, to affect the wild type function of SMS by either destabilizing the SMS dimer/monomer or directly affecting the hydrogen bond network of the active site of SMS. In contrast to these studies, here we report an …

Delphi Web Server: A Comprehensive Online Suite For Electrostatic Calculations Of Biological Macromolecules And Their Complexes., Subhra Sarkar, Shawn Witham, Jie Zhang, Maxim Zhenirovskyy, Walter Rocchia

Publications

Here we report a web server, the DelPhi web server, which utilizes DelPhi program to calculate electrostatic energies and the corresponding electrostatic potential and ionic distributions, and dielectric map. The server provides extra services to fix structural defects, as missing atoms in the structural file and allows for generation of missing hydrogen atoms. The hydrogen placement and the corresponding DelPhi calculations can be done with user selected force field parameters being either Charmm22, Amber98 or OPLS. Upon completion of the calculations, the user is given option to download fixed and protonated structural file, together with the parameter and Delphi output …

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 …

In Silico Investigation Of Ph-Dependence Of Prolactin And Human Growth Hormone Binding To Human Prolactin Receptor, Lin Wang, Shawn Witham, Zhe Zhang, Michael E. Hodsdon, Emil Alexov

Publications

Experimental data shows that the binding of human prolactin (hPRL) to human prolactin receptor (hPRLr-ECD) is strongly pH-dependent, while the binding of the same receptor to human growth hormone (hGH) is pH-independent. Here we carry in silico analysis of the molecular effects causing such a difference and reveal the role of individual amino acids. It is shown that the computational modeling correctly predicts experimentally determined pKa’s of histidine residues in an unbound state in the majority of the cases and the pH-dependence of the binding free energy. Structural analysis carried in conjunction with calculated pH-dependence of the binding revealed that …

Using Delphi Capabilities To Mimic Protein's Conformational Reorganization With Amino Acid Specific Dielectric Constants, Lin Wang, Zhe Zhang, Walter Rocchia, Emil Alexov

Publications

Many molecular events are associated with small or large conformational changes occurring in the corresponding proteins. Modeling such changes is a challenge and requires significant amount of computing time. From point of view of electrostatics, these changes can be viewed as a reorganization of local charges and dipoles in response to the changes of the electrostatic field, if the cause is insertion or deletion of a charged amino acid. Here we report a large scale investigation of modeling the changes of the folding energy due to single mutations involving charged group. This allows the changes of the folding energy to …

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 …