Abstract
Thermal stabilities of DNA duplexes containing Gua (g), α- (a) or β-anomer of formamidopyrimidine-N7-9-hydroxy-aflatoxin B1 (b) differ markedly (Tm: ), but the underlying molecular origin of this experimentally observed phenomenon is yet to be identified and determined. Here, by employing explicit-solvent molecular dynamics simulations coupled with free-energy calculations using a combined linear-interaction-energy/linear-response-approximation approach, we explain the quantitative differences in T in terms of three structural features (bulkiness, order, and compactness) and three energetical contributions (non-polar, electrostatic, and preorganized-electrostatic), and thus advance the current understanding of the relationships between structures, free energies, and thermal stabilities of DNA double helices.
Highlights
Aflatoxin B1 (AFB1 ), systematically (6aR,9aS)-4-methoxy-2,3,6a,9a-tetrahydrocyclopenta[c]furo[30,20 :4,5]furo[2,3-h]chromene-1,11-dione 1 (Figure 1) [1,2], a secondary metabolite [3] produced by aflatoxigenic [3] aspergilli [4,5,6,7,8,9,10] contaminates agricultural commodities [11] in tropical, subtropical, and temperate climate zones [12]
DNA as 2,3-dihydro-2-(N7-guanyl)-9-hydroxy-AFB1 [40,46,48,49,50], leaving behind an abasic site [48], or transforms itself into thermally stable 8,9-dihydro-8-(N5-formyl-20,50,60 -triamino-4-oxo-N5-pyrimidyl)-9-hydroxy-AFB1 5 (FAPy-AFB1 ; Figure 1) [40,43,51,52], which remains firmly attached to the deoxyribose in the native β-anomeric configuration (b) [39,53,54] and restores the original unbent DNA conformation [36,38]
Let us bring to the reader’s attention the main question to which we seek answers in our present, theoretical work, What are the structural and energetical causes, qualitatively and quantitatively, of the experimentally observed differences in the thermal stability of dsDNAg, dsDNAa, and dsDNAb ?, and let us offer the reader an answer: The differences in the melting temperatures (a < g < b) can be explained
Summary
Aflatoxin B1 (AFB1 ), systematically (6aR,9aS)-4-methoxy-2,3,6a,9a-tetrahydrocyclopenta[c]furo[30 ,20 :4,5]furo[2,3-h]chromene-1,11-dione 1 (Figure 1) [1,2], a secondary metabolite [3] produced by aflatoxigenic [3] aspergilli [4,5,6,7,8,9,10] contaminates agricultural commodities (e.g., corn, peanuts, rice, sorghum, and wheat) [11] in tropical, subtropical, and temperate climate zones [12]. DNA as 2,3-dihydro-2-(N7-guanyl)-9-hydroxy-AFB1 [40,46,48,49,50], leaving behind an abasic site [48], or transforms itself (by the opening of the imidazole ring of the modified Gua) into thermally stable 8,9-dihydro-8-(N5-formyl-20 ,50 ,60 -triamino-4-oxo-N5-pyrimidyl)-9-hydroxy-AFB1 5 (FAPy-AFB1 ; Figure 1) [40,43,51,52], which remains firmly attached to the deoxyribose (dRib) in the native β-anomeric configuration (b) [39,53,54] and restores the original unbent DNA conformation [36,38]. The interconversion between b and the alternative α-anomer (a) occurs only in ssDNA [39,53,54], formed upon dissociation of the complementary strands of dsDNA during DNA replication, transcription, and repair. B is a strong mutagen for it is the material cause of the b·C→T·A transversion substitution mutation [46,49,53,64,70,71,72,73,74,75,76,77,78,79,80,81,82], the efficient cause of which is an erroneous bypass of b lesion by the translesion DNA polymerase ζ [64,65]
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