Informatics and standards for nanomedicine technology
Thomas DG, Klaessig F, Harper SL, Fritts M, Hoover MD, Gaheen S, Stokes TH, Reznik-Zellen R, Freund ET, Klemm JD, Paik DS, Baker NA. Informatics and standards for nanomedicine technology. WIRES Nanomedicine and Nanobiotechnology, 3, 511-532, 2011.
There are several issues to be addressed concerning the management and effective use of information (or data), generated from nanotechnology studies in biomedical research and medicine. These data are large in volume, diverse in content, and are beset with gaps and ambiguities in the description and characterization of nanomaterials. In this work, we have reviewed three areas of nanomedicine informatics: information resources; taxonomies, controlled vocabularies, and ontologies; and information standards. Informatics methods and standards in each of these areas are critical for enabling collaboration, data sharing, unambiguous representation and interpretation of data, semantic (meaningful) search and integration of data; and for ensuring data quality, reliability, and reproducibility. In particular, we have considered four types of information standards in this review, which are standard characterization protocols, common terminology standards, minimum information standards, and standard data communication (exchange) formats. Currently, due to gaps and ambiguities in the data, it is also difficult to apply computational methods and machine learning techniques to analyze, interpret and recognize patterns in data that are high dimensional in nature, and also to relate variations in nanomaterial properties to variations in their chemical composition, synthesis, characterization protocols, etc. Progress towards resolving the issues of information management in nanomedicine using informatics methods and standards discussed in this review will be essential to the rapidly growing field of nanomedicine informatics.
- PubMed ID: 21721140
- DOI: 10.1002/wnan.152
On the development of protein pKa calculation algorithms
Carstensen T, Farrell D, Huang Y, Baker NA, Nielsen JE. On the development of protein pKa calculation algorithms. Proteins, 79, 3287-3298, 2011.
Protein pKa calculation methods are developed partly to provide fast non-experimental estimates of the ionization constants of protein side chains. However, the most
significant reason for developing such methods is that a good pKa calculation method is presumed to provide an accurate physical model of protein electrostatics, which can be
applied in methods for drug design, protein design and other structure-based energy calculation methods. We explore the validity of this presumption by simulating the
development of a pKa calculation method using artificial experimental data derived from a human-defined physical reality. We examine the ability of an RMSD-guided
development protocol to retrieve the correct (artificial) physical reality and find that a rugged optimization landscape and a huge parameter space prevent the identification of
the correct physical reality. We examine the importance of the training set in developing pKa calculation methods and investigate the effect of experimental noise on our ability
to identify the correct physical reality, and find that both effects have a significant and detrimental impact on the physical reality of the optimal model identified. Our findings
are of relevance to all structure-based methods for protein energy calculations and simulation, and have large implications for all types of current pKa calculation methods.
Our analysis furthermore suggests that careful and extensive validation on many types of experimental data can go some way in making current models more realistic.
- DOI: 10.1002/prot.23091
- PubMed ID: 21744393
Differential geometry based solvation model II: Lagrangian formulation
Chen Z, Baker NA, Wei GW. Differential geometry based solvation model II: Lagrangian formulation. J Math Biol, 63, 1139-1200, 2011.
Solvation is an elementary process in nature and is of paramount importance to more sophisticated chemical, biological and biomolecular processes. The understanding of solvation is an essential prerequisite for the quantitative description and analysis of biomolecular systems. This work presents a Lagrangian formulation of our differential geometry based solvation model. The Lagrangian representation of biomolecular surfaces has a few utilities/advantages. First, it provides an essential basis for biomolecular visualization, surface electrostatic potential map and visual perception of biomolecules. Additionally, it is consistent with the conventional setting of implicit solvent theories and thus, many existing theoretical algorithms and computational software packages can be directly employed. Finally, the Lagrangian representation does not need to resort to artificially enlarged van der Waals radii as often required by the Eulerian representation in solvation analysis. The main goal of the present work is to analyze the connection, similarity and difference between the Eulerian and Lagrangian formalisms of the solvation model. Such analysis is important to the understanding of the differential geometry based solvation model. The present model extends the scaled particle theory (SPT) of nonpolar solvation model with a solvent-solute interaction potential. The nonpolar solvation model is completed with a Poisson-Boltzmann (PB) theory based polar solvation model. The differential geometry theory of surfaces is employed to provide a natural description of solvent-solute interfaces. The minimization of the total free energy functional, which encompasses the polar and nonpolar contributions, leads to coupled potential driven geometric flow and Poisson-Boltzmann equations. Due to the development of singularities and nonsmooth manifolds in the Lagrangian representation, the resulting potential-driven geometric flow equation is embedded into the Eulerian representation for the purpose of computation, thanks to the equivalence of the Laplace-Beltrami operator in the two representations. The coupled partial differential equations (PDEs) are solved with an iterative procedure to reach a steady state, which delivers desired solvent-solute interface and electrostatic potential for problems of interest. These quantities are utilized to evaluate the solvation free energies and protein-protein binding affinities. A number of computational methods and algorithms are described for the interconversion of Lagrangian and Eulerian representations, and for the solution of the coupled PDE system. The proposed approaches have been extensively validated. We also verify that the mean curvature flow indeed gives rise to the minimal molecular surface (MMS) and the proposed variational procedure indeed offers minimal total free energy. Solvation analysis and applications are considered for a set of 17 small compounds and a set of 23 proteins. The salt effect on protein-protein binding affinity is investigated with two protein complexes by using the present model. Numerical results are compared to the experimental measurements and to those obtained by using other theoretical methods in the literature.
- DOI: 10.1007/s00285-011-0402-z
- PubMed ID: 21279359
25-Hydroxycholesterol increases the availability of cholesterol in phospholipid membranes
Olsen BN, Schlesinger PH, Ory DS, Baker NA. 25-Hydroxycholesterol increases the availability of cholesterol in phospholipid membranes. Biophysical Journal, 100, 948-56, 2011.
Side-chain oxysterols are enzymatically generated oxidation products of cholesterol that serve a central role in mediating cholesterol homeostasis. Recent work has shown that side-chain oxysterols, such as 25-hydroxycholesterol (25-HC), alter membrane structure in very different ways from cholesterol, suggesting a possible mechanism for how these oxysterols regulate cholesterol homeostasis. Here we extend our previous work, using molecular dynamics simulations of 25-HC and cholesterol mixtures in 1-palmitoyl-2-oleoyl-phosphatidylcholine (POPC) bilayers to examine interactions between 25-HC and cholesterol in the same bilayer. When added to cholesterol-containing membranes, 25-HC causes larger changes in membrane structure than when added to cholesterol-free membranes, demonstrating interactions between the two sterols. We also find that the presence of 25-HC changes the position, orientation, and solvent accessibility of cholesterol, shifting it into the water interface and therefore its availability to external acceptors. This is consistent with experimental results showing that oxysterols can trigger cholesterol trafficking from the plasma membrane to the endoplasmic reticulum. These interactions provide a potential mechanism for 25-HC-mediated regulation of cholesterol trafficking and homeostasis through direct modulation of cholesterol availability.
- DOI: 10.1016/j.bpj.2010.12.3728
- PubMed ID: 21320439
Web servers and services for electrostatics calculations with APBS and PDB2PQR
Unni S, Huang Y, Hanson RM, Tobias M, Krishnan S, Li WW, Nielsen JE, Baker NA. Web servers and services for electrostatics calculations with APBS and PDB2PQR. J Comput Chem, 32 (7), 1488-1491, 2011.
APBS and PDB2PQR are widely utilized free software packages for biomolecular electrostatics calculations. Using the Opal toolkit, we have developed a Web services framework for these software packages that enables the use of APBS and PDB2PQR by users who do not have local access to the necessary amount of computational capabilities. This not only increases accessibility of the software to a wider range of scientists, educators, and students but it also increases the availability of electrostatics calculations on portable computing platforms. Users can access this new functionality in two ways. First, an Opal-enabled version of APBS is provided in current distributions, available freely on the web. Second, we have extended the PDB2PQR web server to provide an interface for the setup, execution, and visualization electrostatics potentials as calculated by APBS. This web interface also uses the Opal framework which ensures the scalability needed to support the large APBS user community. Both of these resources are available from the APBS/PDB2PQR website: http://www.poissonboltzmann.org/.
- DOI: 10.1002/jcc.21720
- PubMed ID: 21425296
- PubMed Central ID: PMC3062090
- Download: Preprint (PDF)
APBSmem: A graphical interface for electrostatic calculations at the membrane
Electrostatic forces are one of the primary determinants of molecular interactions. They help guide the folding of proteins, increase the binding of one protein to another and facilitate protein-DNA and protein-ligand binding. A popular method for computing the electrostatic properties of biological systems is to numerically solve the Poisson-Boltzmann (PB) equation, and there are several easy-to-use software packages available that solve the PB equation for soluble proteins. Here we present a freely available program, called APBSmem, for carrying out these calculations in the presence of a membrane. The Adaptive Poisson-Boltzmann Solver (APBS) is used as a back-end for solving the PB equation, and a Java-based graphical user interface (GUI) coordinates a set of routines that introduce the influence of the membrane, determine its placement relative to the protein, and set the membrane potential. The software Jmol is embedded in the GUI to visualize the protein inserted in the membrane before the calculation and the electrostatic potential after completing the computation. We expect that the ease with which the GUI allows one to carry out these calculations will make this software a useful resource for experimenters and computational researchers alike. Three examples of membrane protein electrostatic calculations are carried out to illustrate how to use APBSmem and to highlight the different quantities of interest that can be calculated.
- DOI: 10.1371/journal.pone.0012722
- PubMed ID: 20949122
- PubMed Central ID: PMC2947494
- Download: Preprint (PDF)
Characterization of perfluorooctylbromide-based nanoemulsion particles using atomistic molecular dynamics simulations
Lee, S-J, Olsen BN, Schlesinger PH, Baker NA. Characterization of perfluorooctylbromide-based nanoemulsion particles using atomistic molecular dynamics simulations, J Phys Chem B, 114 (31), 10086-96, 2010.
Perfluorocarbon-based nanoemulsion particles have arisen as promising platforms for the cellular delivery of imaging and therapeutic agents to specific targets. However, current knowledge of the agent delivery mechanism is limited to qualitative and phenomenological models. Lack of detail at the molecular level has hence delayed optimizing or customizing nanoemulsion particles for therapeutic and imaging applications. Here we report the first atomistic structural details of a perfluorooctylbromide-based (PFOB-based) nanoemulsion particle (NEP) with a 1-palmitoyl-2-oleoyl-phosphatidylcholine (POPC) lipid emulsifier. Newly developed PFOB force-field parameters were used in molecular dynamics simulations to model the PFOB-NEP interface in a planar configuration. These PFOB force field parameters were developed and tested to reproduce the characteristics of bulk PFOB as well as PFOB at interfaces with water and emulsifying phospholipids. The modeled PFOB-NEP interface demonstrated significant intercalation of PFOB into the emulsifying lipid monolayer and consequent changes in the structural, electrostatic, and mechanical properties of the POPC monolayer and PFOB. This intercalation provides an explanation for experimental data demonstrating melittin tryptophan fluorescence quenching upon binding to the nanoemulsion particles through the observation of direct contact between the melittin tryptophan and the PFOB bromine. Additionally, the atomistic details of the PFOB-NEP interface structure provided by our simulations are used to suggest the influence of each component on PFOB-NEP delivery function which will be tested in future coarse-grained simulations.
- Pubmed ID: 20684632
- Pubmed Central ID: PMC2917838
- DOI: 10.1021/jp103228c
- Download: Reprint (PDF)
