New theoretical methodology for elucidating the solution structure of peptides from NMR data. 1. The relative contribution of low-energy microstates to the partition function

Hagai Meirovitch, Eva Meirovitch, Jooyoung Lee

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32 Scopus citations

Abstract

Under certain experimental conditions peptide solutions can generate sufficient NMR data for structure determination. Yet, unlike proteins, peptides typically prevail as ensembles of interconverting structures, and therefore, the experimental variables (which are intensities of cross peaks in nuclear Overhauser enhancement spectroscopy (NOESY) spectra, or NOEs) are average quantities. The process of structure elucidation is complex, and many related questions are still open to debate. We have developed a new theoretical methodology for treating ensembles of interconverting conformations which is based on purely thermodynamic grounds. The peptide is described by a potential energy function, and its conformational space is viewed as a collection of microstates, which are local conformational regions around energy minima. The overall methodology enables one to identify the thermodynamically most stable microstates, determine their populations, calculate the individual microstate NOEs, and obtain the overall NOEs as averages over the individual contributions, weighted by the microstate populations. In this paper we develop for the first time theoretical methods for calculating the relative contribution of microstates to the partition function, as their minimum energy is increased above the global energy minimum (GEM). This is necessary for determining which microstates should be considered in detail in the next stage of the analysis. The new methods presented herein are applied to the pentapeptide Leu-enkephalin (H-Tyr-Gly-Gly-Phe-Leu-OH) described by the potential energy function ECEPP, with calculations carried out at 280 K. We find that the microstates contained within relatively small ranges of 2 to 3 kcal/mol above the GEM (or above the lowest harmonic free energy) constitute 0.59 to 0.75 of the partition function. This should be compared with energy ranges up to 15 kcal/mol set arbitrarily in previous studies. A detailed comparison of theoretical predictions with experimental data, obtained from a cryoprotective Leu-enkephalin solution at 280 K, will be carried out in the next paper of this series.

Original languageEnglish
Pages (from-to)4847-4854
Number of pages8
JournalJournal of Physical Chemistry
Volume99
Issue number13
DOIs
StatePublished - 1995
Externally publishedYes

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