Ultrasensitivity of Water Exchange Kinetics to the Size of Metal Ion

Metal ions play a vital role in many biological processes. An important factor in these processes is the dynamics of exchange between ion bound-water molecules and the bulk. Although structural and dynamical properties of labile waters bound to metal ions, such as Na⁺ and Ca²⁺, can be elucidated using molecular dynamics simulations, direct evaluation of rates of exchange of waters rigidly bound to high charge density Mg²⁺, has been elusive. Here, we report a universal relationship, allowing us to determine the water exchange time on metal ions as a function of valence and hydration radius. The proposed relationship, which covers times spanning 14 orders of magnitude, highlights the ultrasensitivity of water lifetime to the ion size, as exemplified by divalent ions, Ca²⁺ (∼100 ps) and Mg²⁺ (∼1.5 μs). We show that even when structures, characterized by radial distributions are similar, a small difference in hydration radius leads to a qualitatively different (associative or dissociative) mechanism of water exchange. Our work provides a theoretical basis for determination of hydration radius, which is critical for accurately modeling the water dynamics around multivalent ions, and hence in describing all electrostatically driven events such as ribozyme folding and catalysis

Molecular Modeling Study on Tunnel Behavior in Different Histone Deacetylase Isoforms

<div><p>Histone deacetylases (HDACs) have emerged as effective therapeutic targets in the treatment of various diseases including cancers as these enzymes directly involved in the epigenetic regulation of genes. However the development of isoform-selective HDAC inhibitors has been a challenge till date since all HDAC enzymes possess conserved tunnel-like active site. In this study, using molecular dynamics simulation we have analyzed the behavior of tunnels present in HDAC8, 10, and 11 enzymes of class I, II, and IV, respectively. We have identified the equivalent tunnel forming amino acids in these three isoforms and found that they are very much conserved with subtle differences to be utilized in selective inhibitor development. One amino acid, methionine of HDAC8, among six tunnel forming residues is different in isoforms of other classes (glutamic acid (E) in HDAC10 and leucine (L) in HDAC 11) based on which mutations were introduced in HDAC11, the less studied HDAC isoform, to observe the effects of this change. The HDAC8-like (L268M) mutation in the tunnel forming residues has almost maintained the deep and narrow tunnel as present in HDAC8 whereas HDAC10-like (L268E) mutation has changed the tunnel wider and shallow as observed in HDAC10. These results explained the importance of the single change in the tunnel formation in different isoforms. The observations from this study can be utilized in the development of isoform-selective HDAC inhibitors.</p> </div

Constructed homology models of HDAC enzymes.

<p>(A) Homology model of HDAC8 (model and template in cyan and green). (B) Homology model of HDAC10 based on 2VQJ (model and template in orange and grey). (C) Homology model of HDAC11 (model and template in yellow and pink). The co-crystallized inhibitor molecules that were copied into models during homology modeling process are shown in stick form.</p

System details of each model for MD simulations.

<p>System details of each model for MD simulations.</p

A diagrammatic representation of ligand binding at the tunnel-like active site of HDAC8.

<p>The binding of SAHA, the first FDA approved drug for HDAC inhibition, along with arrangement of charge relay system and tunnel-forming residues and their interactions with the ligand are denoted.</p

Key geometric parameters used for validation of the HDAC10 and HDAC11 models.

a<p>G-factor – goodness factor and this value should be >−0.5 for a good model.</p

Sequence alignment of HDAC8, 10, and 11 enzymes.

<p>Sequence alignment of HDAC8, 10, and 11 enzymes.</p