Parmbsc1: a refined force field for DNA simulations

We present parmbsc1, a force field for DNA atomistic simulation, which has been parameterized from high-level quantum mechanical data and tested for nearly 100 systems (representing a total simulation time of ~140 μs) covering most of DNA structural space. Parmbsc1 provides high-quality results in diverse systems. Parameters and trajectories are available at http://mmb.irbbarcelona.org/ParmBSC1/

Noncovalent Interactions of Hydrated DNA and RNA Mapped by 2D-IR Spectroscopy

Biomolecules couple to their aqueous environment through a variety of noncovalent interactions. Local structures at the surface of DNA and RNA are frequently determined by hydrogen bonds with water molecules, complemented by non-specific electrostatic and many-body interactions. Structural fluctuations of the water shell result in fluctuating Coulomb forces on polar and/or ionic groups of the biomolecular structure and in a breaking and reformation of hydrogen bonds. Two-dimensional infrared (2D-IR) spectroscopy of vibrational modes of DNA and RNA gives insight into local hydration geometries, elementary molecular dynamics, and the mechanisms behind them. In this chapter, recent results from 2D-IR spectroscopy of native and artificial DNA and RNA are presented, together with theoretical calculations of molecular couplings and molecular dynamics simulations. Backbone vibrations of DNA and RNA are established as sensitive noninvasive probes of the complex behavior of hydrated helices. The results reveal the femtosecond fluctuation dynamics of the water shell, the short-range character of Coulomb interactions, and the strength and fluctuation amplitudes of interfacial electric fields.Comment: To appear as Chapter 8 of Springer Series in Optical Sciences: Coherent Multidimensional Spectroscopy -- Editors: Cho, Minhaeng (Ed.), 201

The Effect of Macromolecular Crowding, Ionic Strength and Calcium Binding on Calmodulin Dynamics

The flexibility in the structure of calmodulin (CaM) allows its binding to over 300 target proteins in the cell. To investigate the structure-function relationship of CaM, we combined methods of computer simulation and experiments based on circular dichroism (CD) to investigate the structural characteristics of CaM that influence its target recognition in crowded cell-like conditions. We developed a unique multiscale solution of charges computed from quantum chemistry, together with protein reconstruction, coarse-grained molecular simulations, and statistical physics, to represent the charge distribution in the transition from apoCaM to holoCaM upon calcium binding. Computationally, we found that increased levels of macromolecular crowding, in addition to calcium binding and ionic strength typical of that found inside cells, can impact the conformation, helicity and the EF hand orientation of CaM. Because EF hand orientation impacts the affinity of calcium binding and the specificity of CaM's target selection, our results may provide unique insight into understanding the promiscuous behavior of calmodulin in target selection inside cells.Comment: Accepted to PLoS Comp Biol, 201

Subcellular localization of the interaction between the human immunodeficiency virus transactivator Tat and the nucleosome assembly protein 1

The histone chaperone nucleosome assembly protein, hNAP-1, is a host cofactor for the activity of the human immunodeficiency virus type 1 (HIV-1) transactivator Tat. The interaction between these two proteins has been shown to be important for Tat-mediated transcriptional activation and for efficient viral infection. Visualization of HIV-1 transcription and fluorescence resonance energy transfer experiments performed in this work demonstrate that hNAP-1 is not recruited to the site of Tat activity but the two proteins interact at the nuclear rim. These data are consistent with a mechanism that requires hNAP-1 for the transport of Tat within the nucleus rather than for the remodeling of nucleosomes on the provirus. Protein-protein docking and molecular modeling of the complex suggest that this interaction occurs between the basic domain of Tat and the histone-binding domain. The combination of theoretical and whole cell studies provided new insights into the functional significance of the Tat:hNAP-1 recognition

Sequence-dependent structural properties of B-DNA: what have we learned in 40 years?

The structure of B-DNA, the physiological form of the DNA molecule, has been a central topic in biology, chemistry and physics. Far from uniform and rigid, the double helix was revealed as a flexible and structurally polymorphic molecule. Conformational changes that lead to local and global changes in the helix geometry are mediated by a complex choreography of base and backbone rearrangements affecting the ability of the B-DNA to recognize ligands and consequently on its functionality. In this sense, the knowledge obtained from the sequence-dependent structural properties of B-DNA has always been thought crucial to rationalize how ligands and, most notably, proteins recognize B-DNA and modulate its activity, i.e. the structural basis of gene regulation. Honouring the anniversary of the first high-resolution X-ray structure of a B-DNA molecule, in this contribution, we present the most important discoveries of the last 40 years on the sequence-dependent structural and dynamical properties of B-DNA, from the early beginnings to the current frontiers in the field