editorial …downloads.hindawi.com/journals/bmri/2012/709085.pdfcomputational methods, from systems...

Hindawi Publishing CorporationJournal of Biomedicine and BiotechnologyVolume 2012, Article ID 709085, 2 pagesdoi:10.1155/2012/709085

Editorial

Advanced Computational Methods in Molecular Medicine

Alejandro Giorgetti,1, 2 Paolo Ruggerone,3 Sergio Pantano,4 and Paolo Carloni5

1 Department of Biotechnology, University of Verona, Strada Le Grazie 15, 37134 Verona, Italy2 Computational Biophysics, German Research School for Simulation Sciences, 52425 Julich, Germany3 CNR-IOM, Unita SLACS and Department of Physics, University of Cagliari, S.P. Monserrato-Sestu km 0.700,09042 Monserrato, Italy

4 Group of Biomolecular Simulations, Institut Pasteur de Montevideo, Mataojo 2020, 11400 Montevideo, Uruguay5 Computational Biophysics, German Research School for Simulation Sciences, and Institute for Advanced Simulation,Forschungszentrum Julich, 52425 Julich, Germany

Correspondence should be addressed to Paolo Carloni, [email protected]

Received 26 January 2012; Accepted 26 January 2012

Copyright © 2012 Alejandro Giorgetti et al. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.

The dauntingly complex functioning of human cells is oftenthe outcome of several molecular processes. Understandingsuch processes is crucial for modern drug discovery, defininginteraction cascades, assessing the effects of mutationschanges in local concentrations of ligands, and so forth.Computational methods, from systems biology to bioinfor-matics and molecular simulation, allow to access featuresdifficult or impossible to be measured. Models (if properlyvalidated against experimental data) help understand theintricate molecular mechanisms of life processes. Bolsteringthe predictive power of these models calls upon the com-putational biologist to improve algorithms and methods.This issue reports on procedures and on applications facingcurrent challenges in computational biology.

Modern biological sciences are becoming more andmore multidisciplinary. At the same time, theoretical andcomputational approaches gain in reliability and their fieldof application widens. O. Fisette at al. discuss recent advancesin the areas of solution nuclear magnetic resonance (NMR)spectroscopy and molecular dynamics (MD) simulationsthat were made possible by the synergistic combination ofboth methods.

Interaction of proteins is of vital importance for manycellular processes and when altered may cause significanthealth problems, thus the availability of reliable toolsto predict and study the determinants of protein-proteininteractions is needed. In this regard, X. -Y. Meng et al.present a newly adapted, computationally efficient BrownianDynamics- (BD-) based protein docking method for predict-ing native protein complexes. The approach includes global

BD conformational sampling, compact complex selection,and local energy minimization. A shell-based grid force fieldrepresents the receptor protein and solvation effects, partiallyconsidering protein flexibility.

Hybrid quantum mechanics/molecular mechanics (QM/MM) calculations are routinely used to study quantum me-chanical processes in biological systems. J. Kang et al. presenta review paper describing an UNIX shell-based interface pro-gram connecting two widely used QM and MM calculationengines, GAMESS and AMBER. The tool was used to inves-tigate a metalloenzyme, azurin, and PU.1-DNA complex andmechanisms of hydrolysis (editing reaction) in leucyl-tRNAsynthetase complexed with the mis-aminoacylated tRNALeu.The authors investigate the influence of environmental ef-fects on the electronic structure.

Electron transfer in proteins constitutes key steps inseveral biological processes, ranging from photosynthesis toaerobic respiration. T. Hayashi and A. Stuchebrukhov inves-tigate electron tunneling in NADH : ubiquinone oxidoreduc-tase (Complex I), a key enzyme in cellular respiration as anentry point of the electron transport chain of mitochondriaand bacteria, by evaluating the transition flux between donorand acceptor at atomistic resolution. The study suggeststhat the diffusion of internal water molecules dynamicallycontrols tunneling efficiency.

Methionine sulfoxide reductases (Msr), if reduced bytheir biological partner, thioredoxin (Trx), act extremelyefficient as members of the cellular antioxidant defensesystem. To understand the Trx-induced reduction mech-anism, structural aspects of the intermolecular complex

2 Journal of Biomedicine and Biotechnology

formation between mammalian MsrB1 and Trx were studiedby Dobrovolska et al., combining NMR spectroscopy andbiocomputing. According to the authors, the intermediateMsrB1/Trx complex is stabilized by interprotein β-layer. Thecomplex formation accompanied by distortion of disulfidebond within MsrB1 facilitates the reduction of oxidizedMsrB1.

Integrins have been shown to play a crucial role in pro-moting tumor growth and metastasis, regulating angiogen-esis—the growth of new blood vessels—and lymphangiog-enesis—the growth of new lymphatic vessels. Thus, the workof M. Freindorf and coworkers on the binding of a series ofhormone analogues to the αvβ3 integrin represents a furthercontribution to the understanding of such fundamentalregulators of biological tissues. Using QM/MM methods theauthors identified for the ligands considered here multiplemodes of binding near the arginine-glycine-aspartate (RGD)recognition site of αvβ3 integrin. This observation indicatesthat there may be subtle changes in the integrin-bindingsite that can govern binding to alternate sites, influencingdownstream signaling pathway.

The paper by F. Fogolari et al. discusses technical aspectsof molecular dynamics simulations in the aqueous phase per-formed at high solute concentrations. These conditions areoften present in molecular recognition processes. The paperprovides specific examples, ranging from the association ofbeta-2 microglobulins to the binding of hydrogen peroxideto its target glutathione peroxidase.

Membrane proteins are the principal targets of the avail-able drugs in the market, yet structural information is avail-able for very few of them. Feature predictions are thereforevery important for drug development. D. Mukherjee et al.use Artificial Neural Network (ANN) for the prediction ofmechanisms of intracellular protein sorting.

Martinez-Archundia et al. uncovered the role of keyresidues for the function of a membrane receptor, that is,the human M3 muscarinic acetylcholine receptor. The three-dimensional structure of the receptor was built by homologymodeling, using the crystallographic structure of bovinerhodopsin as a template. Site mutagenesis experiments wereperformed to assess the role of two residues, F222 and T235,which are strong candidates for the recognition of ligands.The combined experimental-computational approach con-firmed the involvement of both residues in modulating thebinding affinity of the ligand.

A rapidly growing number of protein structures iscurrently deposited in the PDB database in the ambit ofstructural genomics consortiums. However, the molecularfunction of the proteins may be neither known nor validatedby experiment. Schuller and coworkers apply an integratedbioinformatics tool to transcriptional regulators controllingthe expression of genes involved in diverse biological func-tions of bacteria. They provide a functional classification tofactors with known 3D structure but unknown function.

In closing this survey, we would like to mention that backin the late forties, Linus Pauling and coworkers published apaper in Science on “sickle cell anemia, a molecular disease.”This contribution kicked off the field of experimentalmolecular medicine. More than sixty years after Pauling’s

seminal paper, we observe that computational approacheshave become extremely powerful tools, complementary toexperiment, to uncover molecular mechanisms of diseasesand to thrive strategies to counteract them.

Acknowledgment

German Research School for Simulation Sciences is a jointventure of RWTH Aachen University and Forschungszen-trum Julich, Germany.

Alejandro GiorgettiPaolo Ruggerone

Sergio PantanoPaolo Carloni

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