Unraveling the sequence-dependent polymorphic behavior of d(CpG) steps in B-DNA.

We have made a detailed study of one of the most surprising sources of polymorphism in B-DNA: the high twist/low twist (HT/LT) conformational change in the d(CpG) base pair step. Using extensive computations, complemented with database analysis, we were able to characterize the twist polymorphism in the d(CpG) step in all the possible tetranucleotide environment. We found that twist polymorphism is coupled with BI/BII transitions, and, quite surprisingly, with slide polymorphism in the neighboring step. Unexpectedly, the penetration of cations into the minor groove of the d(CpG) step seems to be the key element in promoting twist transitions. The tetranucleotide environment also plays an important role in the sequence-dependent d(CpG) polymorphism. In this connection, we have detected a previously unexplored intramolecular C-H···O hydrogen bond interaction that stabilizes the low twist state when 3'-purines flank the d(CpG) step. This work explains a coupled mechanism involving several apparently uncorrelated conformational transitions that has only been partially inferred by earlier experimental or theoretical studies. Our results provide a complete description of twist polymorphism in d(CpG) steps and a detailed picture of the molecular choreography associated with this conformational change.

Breathing, bubbling, and bending: DNA flexibility from multimicrosecond simulations.

Bending of the seemingly stiff DNA double helix is a fundamental physical process for any living organism. Specialized proteins recognize DNA inducing and stabilizing sharp curvatures of the double helix. However, experimental evidence suggests a high protein-independent flexibility of DNA. On the basis of coarse-grained simulations, we propose that DNA experiences thermally induced kinks associated with the spontaneous formation of internal bubbles. Comparison of the protein-induced DNA curvature calculated from the Protein Data Bank with that sampled by our simulations suggests that thermally induced distortions can account for ~80% of the DNA curvature present in experimentally solved structures.

A hybrid all-atom/coarse grain model for multiscale simulations of DNA.

Hybrid simulations of molecular systems, which combine all-atom (AA) with simplified (or coarse grain, CG) representations, propose an advantageous alternative to gain atomistic details on relevant regions while getting profit from the speedup of treating a bigger part of the system at the CG level. Here we present a reduced set of parameters derived to treat a hybrid interface in DNA simulations. Our method allows us to forthrightly link a state-of-the-art force field for AA simulations of DNA with a CG representation developed by our group. We show that no modification is needed for any of the existing residues (neither AA nor CG). Only the bonding parameters at the hybrid interface are enough to produce a smooth transition of electrostatic, mechanic and dynamic features in different AA/CG systems, which are studied by molecular dynamics simulations using an implicit solvent. The simplicity of the approach potentially permits us to study the effect of mutations/modifications as well as DNA binding molecules at the atomistic level within a significantly larger DNA scaffold considered at the CG level. Since all the interactions are computed within the same classical Hamiltonian, the extension to a quantum/classical/coarse-grain multilayer approach using QM/MM modules implemented in widely used simulation packages is straightforward.