Optimal molecular structures of prion AGAAAAGA amyloid fibrils formatted by simulated annealing

Abstract

To date, there is little structural data available on the AGAAAAGA palindrome in the hydrophobic region (113-120) of prion proteins, although many experimental studies have shown that this region has amyloid fibril forming properties. This region belongs to the N-terminal unstructured region (1-123) of prions, the structure of which has proved hard to determine using NMR or X-ray crystallography. This paper reports the successful construction of three amyloid fibril models for this region. The models were formatted by standard simulated annealing using suitable templates from the Protein Data Bank, and were refined using several traditional optimization methods within AMBER. Because the NMR or X-ray structure of the hydrophobic region AGAAAAGA of prion proteins has not yet been determined, these models can be used as a reference for experimental studies on this region. The results presented here confirm standard simulated annealing as an effective tool in molecular modeling. The three constructed models for amyloid fibrils may be useful in furthering the goals of medicinal chemistry in this field.

Computational Potential Energy Minimization Studies on the Prion AGAAAAGA Amyloid Fibril Molecular Structures

“…Thus, it is very amenable to use simulated annealing (SA) to format the models constructed. Zhang (2011aZhang ( , 2011d) presents a hybrid method of global search SA with local steepest descent (SD), conjugate gradient (CG) search. The hybrid method is executed with the following three procedures.…”

Selective bond breaking mediated by state specific vibrational excitation in model HOD molecule through optimized femtosecond IR pulse: A simulated annealing based approach

“…SA, since its proposition as a method, back in 1983, has been used extensively as a serious optimization tool in solving problems of chemistry and physics. [50][51][52][53][54][55][56][57][58][59] In this SA algorithm, the cost function is evaluated at each SA step. If cost function decreases, the move is accepted right away.…”

A novel canonical dual computational approach for prion AGAAAAGA amyloid fibril molecular modeling

“…Many experimental studies such as (Brown, 2000, Brown, 2001, Brown et al, 1994, Holscher et al, 1998, Jobling et al, 2001, Jobling et al, 1999, Kuwata et al, 2003, Norstrom et al, 2005, Wegner et al, 2002 have shown two points: (1) the hydrophobic region (113-120) AGAAAAGA of prion proteins is critical in the conversion from a soluble PrP C into an insoluble PrP Sc fibrillar form; and (2) normal AGAAAAGA is an inhibitor of prion diseases. Various computational approaches were used to address the problems related to "amyloid fibril" (Carter et al, 1998, Chou, 2004b, Chou, 2004c, Chou et al, 2002, Wang et al, 2008, Wei et al, 2005, Zhang, 2011, Zhang, 2009. By introducing novel mathematical canonical dual formulations and computational approaches, in this paper we may construct atomic-resolution molecular structures for prion (113-120) AGAAAAGA amyloid fibrils.…”

“…Various computational molecular dynamics approaches have been used to study PrP (106-126) (Kuwata et al, 2003, Wagoner 2010) but, to the best of our knowledge, to predict molecular structures of prion AGAAAAGA amyloid fibrils the computational approaches are few (Zhang, 2011. Zhang (2011) successfully constructed three AGAAAAGA amyloid fibril models by the standard simulated annealing (SA) method and several traditional optimization methods within AMBER 10 package.…”

“…It is even no need to do furthermore SDCG refinements by the AMBER package. We could not do comparisons (for example, the angstrom values between adjacent β-sheets and β-strands) for the models of (Zhang, 2011 and of this paper, because these models have different number of chains and different structural Classes listed in (Kuwata et al, 2003).…”