Extension of the AMBER force field to cyclic α,α dialkylated peptides

Abstract

The popular biomolecular AMBER (ff99SB) force field (FF) has been extended with new parameters for the simulations of peptides containing α,α dialkylated residues with cyclic side chains. Together with the recent set of nitroxide parameters [E. Stendardo, A. Pedone, P. Cimino, M. C. Menziani, O. Crescenzi and V. Barone, Phys. Chem. Chem. Phys., 2010, 12, 11697] this extension allows treating the TOAC residue (TOAC, 2,2,6,6-tetramethylpiperidine-1-oxyl-4-amino-4-carboxylic acid) widely used as a spin label in protein studies. All the conformational minima of the Ac-Ac(6)C-NMe (Ac = acetyl, Ac(6)C = 1-aminocyclohexaneacetic acid, NMe = methylamino) and Ac-TOAC-NMe dipeptides have been examined in terms of geometry and relative energy stability by Quantum Mechanical (QM) computations employing an hybrid density functional (PBE0) for an extended training set of conformers with various folds. A very good agreement between QM and MM (molecular mechanics) data has been obtained in most of the investigated properties, including solvent effects. Finally, the new set of parameters has been validated by comparing the conformational and dynamical behavior of TOAC-labeled polypeptides investigated by means of classical molecular dynamics (MD) simulations with QM data and experimental evidence. The new FF accurately describes the tuning of conformational and dynamical behavior of the Ac-TOAC-NMe dipeptide and double spin-labeled heptapeptide Fmoc-(Aib-Aib-TOAC)(2)-Aib-OMe (Fmoc, fluorenyl-9-methoxycarbonyl; Aib, α-aminoisobutyric acid; OMe, methoxy) by solvents with different polarity. In particular, we found that the 3(10) helical structure of heptapeptide is the most stable one in vacuo, with a geometry very similar to the X-ray crystallographic structure, whereas a conformational equilibrium between the 3(10)- and α-helical structures is established in aqueous solution, in agreement with EPR data.

Development of second generation peptides modulating cellular adiponectin receptor responses

“…Atom types and partial atomic charges for norvaline were derived from leucine and isoleucine. Force field parameters for Chex were obtained from Grubisic et al ( 2012 ). Atom types for Dab were derived from lysine and the atomic partial charges were calculated with YASARA AutoSMILES ( www.yasara.org/autosmiles ).…”

Tailor‐made computational protocols for precise characterization of small biological building blocks using QM and MM approaches

“…While earlier studies mainly focused on TOAC incorporation into short peptides, recently devised method by Karim et al, for introducing TOAC into proteins has opened promising avenues for its novel applications in protein research. In the following, we report recently extended AMBER FF parameters that facilitate the investigation of TOAC substituted polypeptides …”

“…The choice of PBE0 functional was driven by proven accurate estimations of several physico‐chemical observables of polypeptides as shown before . Further, three new atom types (CJ,CL, and H6, refer Figure ) were introduced into AMBER ff99SB, whose van der Waals parameters (for CJ, H6) and the torsional parameters (for CJ) were re‐derived with high level QM calculations . The nitroxide parameters were adopted from that of the six‐membered TEMPO skeleton ((2,2, 6,6‐tetramethyl piperidin‐1‐yl)oxidanyl) parameterized in AMBER .…”

Chapter 9. First Principles Methods in Biology: From Continuum Models to Hybrid Ab initio Quantum Mechanics/Molecular Mechanics

“…Only in a few cases, classical models, usually derived from ad hoc fitting procedures versus QM data, have been tailored towards at least a class of chemical compounds, as in the case of nitroxide based radicals. [359][360][361] Especially within the molecules of biological interest, there are many examples of radical species of amino acids and DNA or RNA bases that are involved in relevant enzymatic reactions, electron transfer processes, 362 ultra-violet radiation-mediated DNA damages. 363,364 One wants to describe, at molecular level, the role of stereo-electronic, dynamical, and environmental effects in tuning the structure and magnetic properties of such radicals in aqueous solution.…”