Helix Formation in a Pentapeptide: Experiment and Force-field Dependent Dynamics

Abstract

We used a combined approach of experiment and simulation to determine the helical population and folding pathway of a small helix forming blocked pentapeptide, Ac-(Ala)(5)-NH(2). Experimental structural characterization of this blocked peptide was carried out with far UV circular dichroism spectroscopy, FTIR, and NMR measurements. These measurements confirm the presence of the α-helical state in a buffer solution. Direct molecular dynamics and replica-exchange simulations of the pentapeptide were performed using several popular force fields with explicit solvent. The simulations yielded statistically reliable estimates of helix populations, melting curves, folding, and nucleation times. The distributions of conformer populations are used to measure folding cooperativity. Finally, a statistical analysis of the sample of helix-coil transition paths was performed. The details of the calculated helix populations, folding kinetics and pathways vary with the employed force field. Interestingly, the helix populations, folding, and unfolding times obtained from most of the studied force fields are in qualitative agreement with each other and with available experimental data, with the deviations corresponding to several kcal/mol in energy at 300 K. Most of the force fields also predict qualitatively similar transition paths, with unfolding initiated at the C-terminus. Accuracy of potential energy parameters, rather than conformational sampling may be the limiting factor in current molecular simulations.

Probing Selection Mechanism of the Most Favorable Conformation of a Dipeptide in Chaotropic and Kosmotropic Solution

“…The choice of force field is motivated by two factors. First, in our previous simulations of short model peptides use of OPLS/AA parameters led to very good agreement on helix content and folding kinetics with experimental data[36][37][38] . Second, to obtain diffusion coefficients comparable to experimental data, we need to employ a water model with reasonable viscosity and self-diffusion, such as TIP4P39 .Molecular reorientations in MD trajectories were analyzed by generating time series of transition dipole axis for the NATA side-chain 1Lb transition28 and calculating correlations functions C 2 (t) = <3cos 2 θ -1>/2, where θ is the axis reorientation during time t and the average is over starting points.…”

Catch bond-like kinetics of helix cracking: Network analysis by molecular dynamics and Milestoning

“…Long helices are frequently found in molecular machines such as kinesin and myosin, and their stability under load is therefore of considerable biophysical interest. Prior theoretical investigations of helix unfolding were done without load and for shorter helices (5-20 amino acids [1][2][3][4][5][6][7][8][9][10][11][12][13][14].…”

Structure and reorientational dynamics of angiotensin I and II: a microscopic physical insight

“…Therefore as the temperature increases, the equilibrium shifts from the PPII form to an unordered conformation, causing a decrease in intensity (Park et al, 1997;Pujals & Giralt, 2008). Singular value decomposition (SVD) was applied to the combined temperaturedependent CD spectra of both samples to determine the presence of spectral components (Garcia-Mira, Sadqi, Fischer, Sanchez-Ruiz, & Munoz, 2002;Hegefeld et al, 2010;Jas & Kuczera, 2004;Konno, 1998;Sreerama, Venyaminov, & Woody, 2000). Two main components were resolved from the SVD analysis shown in Figures 1B and 2B.…”

“…Using distributed computing, the folding kinetics of the 21-residue Fs peptide has been analyzed (Sorin & Pande, 2005). More recently, both equilibrium and kinetics of folding of the blocked penta-alanine have been simulated using standard modeling tools (Hegefeld, Chen, DeLeon, Kuczera, & Jas, 2010), while folding of several small proteins was followed on a specialized computer system (Piana, Lindorff-Larsen, & Shaw, 2011). Such simulations provide a wealth of microscopic information on peptide and protein behavior, greatly increasing our understanding of the observed properties of these interesting systems.…”