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Vol 44(2010) N 6 p. 958-967;
A.N. Istrate1, A.B. Mantsyzov1, S.A. Kozin2,3, V.I. Polshakov4*

Optimization of the Methods for Small Peptide Solution Structure Determination by NMR Spectroscopy

1Department of Chemistry, Moscow State University, Moscow, 119992 Russia
2Orekhovich Institute of Biomedical Chemistry, Russian Academy of Medical Sciences, Moscow, 119121 Russia
3Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, 119991 Russia
4Faculty of Fundamental Medicine, M.V. Lomonosov Moscow State University, Moscow, 119991 Russia

*vpolsha@mail.ru
Received - 2010-06-29; Accepted - 2010-06-29

NMR spectroscopy was recognized as a method of protein structure determination in solution. However, determination of the conformation of small peptides, which undergo fast molecular motions, remains a challenge. This is mainly caused by the impossibility to collect the required quantity of the distance and dihedral angle restraints from NMR spectra. At the same time, short charged peptides play an important role in a number of biological processes, in particular in pathogenesis of neurodegenerative diseases including Alzheimer's disease. Therefore, development of a method for structure simulation of small peptides in aqueous environment using the most realistic force fields seems to be of current importance. Such algorithm has been developed using the Amber-03 force field and Gromacs program after modification of its code. Calculation algorithm has been verified on a model peptide with a known solution structure and a metal-binding fragment of rat β-amyloid, whose structure has been determined by alternative methods. The developed algorithm substantially increases structure quality, in particular Ramachandran plot statistics, and decreases RMSD of atomic coordinates inside the calculated family. The described protocol can be used for determination of conformation of short peptides, and also for optimization of structure of larger proteins containing poorly structured fragments.

NMR spectroscopy, molecular dynamics, peptide structure, β-amyloid, Alzheimer disease



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