## 3 Results and Discussion
### Main Complexes Formed with Microcystins with High Affinity Scores
#### 3.1.4 Cellular Proliferation and Cancer  
The induction of apoptosis or uncontrolled cell proliferation depends on the exposure to different MC concentrations (dose dependent). The expression of the antiapoptotic gene Bcl-2 increases more than 4000-fold at low concentrations of MC-LR. This generates the  
\begin{table}
\begin{tabular}{c c c c c c} \hline \hline
**MC-LA,** & **MC-LA,** & **MC-LR,** & **MC-LR,** & **MC-LR,** & **MC-LA,** & **MC-LR,** \\
**MC-RR,** & **MC-RR,** & **MC-LR,** & **MC-RR** & **MC-RR** & **MC-LV** \\ \hline Gln 62 & Ala 58 & Ser 61 & Gln 54 & * Gln 362 & Tyr 197 \\ * Tyr 111 & Ser 333 & Ser 100 & Ala 332 & * Thr 496 & \\ Leu 115 & Asn 494 & Trp 201 & Ala 334 & & \\ Tyr 186 & Val 495 & * Arg 381 & Tyr 501 & & \\ Pro 497 & & & & & \\ Arg 500 & & & & & \\ \hline \hline \end{tabular}
\end{table}
Table 2: Key bonding residues on ACE-microcystin complexes.  
Figure 5: Three-dimensional representation of the CYP3A4 and MC–LY complex. Contact residues at the binding site and interactions predicted by Ligand Scout are shown on the right. Atoms are colored with the CPK scheme.  
survival of tumors in response to chemotherapy [60]. In contrast, high concentrations of MC-LR induce a reduction in the expression of the gene Bcl-22, which leads to apoptosis [61].  
We found strong interactions between the four variants and MCL-1, a protein that belongs to the Bcl-2 family as well as with kinases MST4, CLK1, and LIMK1. The mechanisms of action of MCs that lead to cell proliferation and carcinogenesis are not well understood. However, MCs seem to share a similar biochemical effect by inducing the activation of antiapoptotic signaling pathways, alteration of the cell cycle, and inhibition of PP1 and PP2A, which causes an altered protein phosphorylation/dephosphorylation balance [33; 62].  
CLK1 is implicated in the pathophysiology of Alzheimer's disease through phosphorylation of serine residues in SR proteins [63]. Therefore, these proteins can be considered to be potential targets of the neurological disorders originated by direct interaction with MCs. Downregulation of LIMK1 is associated with fibrosis, psoriatic epidermal proliferation, and different types of carcinogenesis [64; 65]. The interaction of MCs with LIMK1 could explain the molecular mechanisms associated with different types of fibrosis, from psoriatic epidermal proliferation [63] to vascular heart disease [53; 65].  
A strong interaction was found between MC-RR with the selenoprotein thioredoxin reductase TRXR1, which regulates the p53 activity and has a high metastatic potential [66; 67]. Alteration of TRXR1 levels or activity is accompanied by pro-oxidative changes in the cell, inducing increased oxidative stress, and thus, damage to different biomolecules [66; 68].  
The theoretical results obtained in this study are consistent with experimental observations reported by different authors [11; 12; 26; 42; 62]. The interactions reported here provide an important perspective of the possible alterations generated by the presence of MC variants or the synergistic effect of them. Furthermore, we were able to quantify binding affinities, describe the types of bonds of MC-enzyme/protein complexes, and thus explore in detail the interactions of the ligand with the active site of the enzyme or protein in general. In short, the affinity of MCs to different receptors that generate similar effects represents a greater potential risk to these toxins.