[gmx-users] Re: oplsaa vs. charmm (Thomas Evangelidis)

[Ran Friedman]

Hi,

You may want to look at the papers below, which deal with a similar problem.
Also, I would run multiple simulations for each case.

Ran.

@Article{ScherzerAttali:2010:PLoS-One:20559435,
author = "Scherzer-Attali, R and Pellarin, R and Convertino, M and Frydman-Marom, A and Egoz-Matia, N and Peled, S and Levy-Sakin, M and Shalev, D E and Caflisch, A and Gazit, E and Segal, D",
title = {Complete phenotypic recovery of an Alzheimer's disease model by a quinone-tryptophan hybrid aggregation inhibitor},
abstract = {The rational design of amyloid oligomer inhibitors is yet an unmet drug development need. Previous studies have identified the role of tryptophan in amyloid recognition, association and inhibition. Furthermore, tryptophan was ranked as the residue with highest amyloidogenic propensity. Other studies have demonstrated that quinones, specifically anthraquinones, can serve as aggregation inhibitors probably due to the dipole interaction of the quinonic ring with aromatic recognition sites within the amyloidogenic proteins. Here, using in vitro, in vivo and in silico tools we describe the synthesis and functional characterization of a rationally designed inhibitor of the Alzheimer's disease-associated beta-amyloid. This compound, 1,4-naphthoquinon-2-yl-L-tryptophan (NQTrp), combines the recognition capacities of both quinone and tryptophan moieties and completely inhibited Abeta oligomerization and fibrillization, as well as the cytotoxic effect of Abeta oligomers towards cultured neuronal cell line. Furthermore, when fed to transgenic Alzheimer's disease Drosophila model it prolonged their life span and completely abolished their defective locomotion. Analysis of the brains of these flies showed a significant reduction in oligomeric species of Abeta while immuno-staining of the 3(rd) instar larval brains showed a significant reduction in Abeta accumulation. Computational studies, as well as NMR and CD spectroscopy provide mechanistic insight into the activity of the compound which is most likely mediated by clamping of the aromatic recognition interface in the central segment of Abeta. Our results demonstrate that interfering with the aromatic core of amyloidogenic peptides is a promising approach for inhibiting various pathogenic species associated with amyloidogenic diseases. The compound NQTrp can serve as a lead for developing a new class of disease modifying drugs for Alzheimer's disease.},
journal = "PLoS One",
year = "2010",
volume = "5",
number = "6",
pages = "",
month = "",
pmid = "20559435",
url = "http://www.hubmed.org/display.cgi?uids=20559435",
doi = "10.1371/journal.pone.0011101"
}
@Article{Convertino:2009:Protein-Sci:19309732,
author = "Convertino, M and Pellarin, R and Catto, M and Carotti, A and Caflisch, A",
title = {9,10-Anthraquinone hinders beta-aggregation: how does a small molecule interfere with Abeta-peptide amyloid fibrillation?},
abstract = {Amyloid aggregation is linked to a number of neurodegenerative syndromes, the most prevalent one being Alzheimer's disease. In this pathology, the beta-amyloid peptides (Abeta) aggregate into oligomers, protofibrils, and fibrils and eventually into plaques, which constitute the characteristic hallmark of Alzheimer's disease. Several low-molecular-weight compounds able to impair the Abeta aggregation process have been recently discovered; yet, a detailed description of their interactions with oligomers and fibrils is hitherto missing. Here, molecular dynamics simulations are used to investigate the influence of two relatively similar tricyclic, planar compounds, that is, 9, 10-anthraquinone (AQ) and anthracene (AC), on the early phase of the aggregation of the Abeta heptapeptide segment H(14)QKLVFF(20), the hydrophobic stretch that promotes the Abeta self-assembly. The simulations show that AQ interferes with beta-sheet formation more than AC. In particular, AQ intercalates into the beta-sheet because polar interactions between the compound and the peptide backbone destabilize the interstrand hydrogen bonds, thereby favoring disorder. The thioflavin T-binding assay indicates that AQ, but not AC, sensibly reduces the amount of aggregated Abeta(1-40) peptide. Taken together, the in silico and in vitro results provide evidence that structural perturbations by AQ can remarkably affect ordered oligomerization. Moreover, the simulations shed light at the atomic level on the interactions between AQ and Abeta oligomers, providing useful insights for the design of small-molecule inhibitors of aggregation with therapeutic potential in Alzheimer's disease.},
journal = "Protein Sci",
year = "2009",
volume = "18",
number = "4",
pages = "792-800",
month = "Apr",
pmid = "19309732",
url = "http://www.hubmed.org/display.cgi?uids=19309732",
doi = "10.1002/pro.87"
}
------------------------------------------------
Ran Friedman
Biträdande Lektor (Assistant Professor)

Linnaeus University
School of Natural Sciences
391 82 Kalmar, Sweden

Norrgård, room 328d
+46 480 446 290 Telephone
+46 76 207 8763 Mobile
ran.friedman at lnu.se
http://lnu.se/ccbg
------------------------------------------------
-------------------------------------------------------------
From: Thomas Evangelidis <tevang3 at gmail.com>
Subject: Re: [gmx-users] oplsaa vs. charmm
To: Discussion list for GROMACS users <gmx-users at gromacs.org>
Message-ID: <BANLkTimeav_=SK5JMhP-TGcx-iyCDJAiyw at mail.gmail.com>
Content-Type: text/plain; charset="iso-8859-1"

Thank you all for your comments! Let me give you more details about my case:

I want to study the interaction modes of known inhibitors with the monomeric
state of an IDP (~100 aa). IDPs only assume secondary structure when in
complex with their partners, hence there are no crystal structures of the
protein as a monomer. The only experimental data that exist are NMR and CD
data of a close homologue (~78% sequence identity) which show that the
monomer is partially folded in the following simplified pattern:

CHHHHHHHHCCCCCCCChhHHHhhhC

where "h" denotes transient helix, "H" relative rigid helix, and "C" random
coil. The whole IDP is ~100 aa, but we have indications that the inhibitors
bind to the central disordered 40 aa. Therefore I was thinking of running
two simulations, one for the whole ~100 aa using secondary restraints
wherever applicable, and a longer one for the central 40 amino acids. The
problem with the whole-IDP simulation is that the unfolded ~100 aa will
occupy substantially bigger space than the central 40 aa, therefore the
dimensions of the box will be larger and will include much more solvent.
This will make the simulation cumbersome and I won't be able to do enough
sampling for the whole IDP.

In both simulations I am thinking of keeping the desired amino acids from
the crystal structure of the IDP in complex with its partner, carry out REMD
to unfold it, and then add an inhibitor to see where it binds.


You comments about the proposed protocol, force field and water model to
use, will be highly appreciated!

thanks,
Thomas