Component of Cannabis, Cannabidiol, as a Possible Drug against the Cytotoxicity of Aβ(31–35) and Aβ(25–35) Peptides: An Investigation by Molecular Dynamics and Well-Tempered Metadynamics Simulations

Abstract

In this work cannabidiol (CBD) was investigated as a possible drug against the cytotoxicity of Aβ(31–35) and Aβ(25–35) peptides with the help of atomistic molecular dynamics (MD) and well-tempered metadynamics simulations. Four interrelated mechanisms of possible actions of CBD are proposed from our computations. This implies that one mechanism can be a cause or/and a consequence of another. CBD is able to decrease the aggregation of peptides at certain concentrations of compounds in water. This particular action is more prominent for Aβ(25–35), since originally Aβ(31–35) did not exhibit aggregation properties in aqueous solutions. Interactions of CBD with the peptides affect secondary structures of the latter ones. Clusters of CBD are seen as possible adsorbents of Aβ(31–35) and Aβ(25–35) since peptides are tending to aggregate around them. And last but not least, CBD exhibits binding to MET 35 . All four mechanisms of actions can possibly inhibit the Aβ-cytotoxicity as discussed in this paper. Moreover, the amount of water also played a role in peptide clustering: with a growing concentration of peptides in water without a drug, the aggregation of both Aβ(31–35) and Aβ(25–35) increased. The number of hydrogen bonds between peptides and water was significantly higher for simulations with Aβ(25–35) at the higher concentration of peptides, while for Aβ(31–35) that difference was rather insignificant. The presence of CBD did not substantially affect the number of hydrogen bonds in the simulated systems.

Two statins and cromolyn as possible drugs against the cytotoxicity of Aβ(31–35) and Aβ(25–35) peptides: a comparative study by advanced computer simulation methods

“…In particular, combinations of extended conformations and isolated b-bridges are related to peptide aggregation. 31,42,61,62 A larger amount of such secondary structures is observed in Fig. 6(a) and (c) for Ab (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35), which can be correlated with its aggregation (see the RDFs in Fig.…”

“…Such a property was also observed in simulations with cannabidiol. 42 The positive outcome of this can be that all the peptides aggregate on the drugs instead of the surfaces of neuronal membranes, which could save neurons from their death. If this is an important ability of the drugs, then the well-tempered metadynamics simulations indicate that cromolyn would be the most efficient drug to form such clusters and keep the peptides away from the neural membranes.…”

“…Nevertheless, there are not many atomistic modeling works carried out with Aβ(25–35) and Aβ(31–35). 40–43 For instance, in our other in silico paper by Chrobak et al , 42 we elucidated how cannabidiol interacts with Aβ(31–35) and Aβ(25–35). Furthermore, Ermilova et al 43 investigated Aβ(25–35) in the presence of a lipid membrane and discovered that in the presence of cholesterol, peptides aggregate on the membrane surface.…”

“…From both computational and experimental studies, it is known that Ab (31)(32)(33)(34)(35) is a peptide which does not build clusters. 31,42 The cytotoxicity of Ab (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) is related to other features of the peptide as well, from the order of the sequence to the presence of MET 35 in the C-terminal. In fact, the presence and the position of MET 35 are seen as the reason for the toxicity of both Ab (31)(32)(33)(34)(35) and Ab (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35).…”

“…Nevertheless, there are not many atomistic modeling works carried out with Ab (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) and Ab (31)(32)(33)(34)(35). [40][41][42][43] For instance, in our other in silico paper by Chrobak et al, 42 we elucidated how cannabidiol interacts with Ab (31)(32)(33)(34)(35) and Ab (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35). Furthermore, Ermilova et al 43 investigated Ab (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) in the presence of a lipid membrane and discovered that in the presence of cholesterol, peptides aggregate ...…”