Biomedical subjects

Mark E Tuckerman

Publications and source records attributed to Mark E Tuckerman.

3 recordsLinked to original sources

PubMed2003

Molecular dynamics study of the connection between flap closing and binding of fullerene-based inhibitors of the HIV-1 protease.

The complementary spatial relationship between fullerene C(60) and the hydrophobic cavity region of the human immunodeficiency virus (HIV) protease, which houses the active site of the enzyme, has led to the suggestion that fullerene-based derivatives could have potential use as effective HIV protease inhibitors. The ability of such compounds to desolvate the cavity region leads to a strong hydrophobic interaction between the C(60) moiety and residues in the cavity region. In this study, the connection between the motion of the so-called flexible flaps of the cavity and favorable binding of a fullerene-based protease inhibitor is explored using multiple-time scale molecular dynamics simulations and free energy techniques. In addition, the effect of the interaction between the C(60) moiety and the residues in the cavity region on the water content of the cavity is also investigated. Conformational free energy profiles along a suitably chosen flap opening coordinate show a considerable barrier to flap opening in the presence of the inhibitor, while no such barrier exists for the protease alone. This result is interpreted in terms of a strong hydrophobic interaction between the C(60) moiety and the flexible flaps, which cause the latter to close tightly around the inhibitor, thereby expelling water from the cavity and leading to a favorable binding interaction. This interpretation is rationalized by direct analysis of the water content in the cavity in the presence and absence of the inhibitor.

Binding, Competitive↗

PubMed2002

The nature and transport mechanism of hydrated hydroxide ions in aqueous solution.

Compared to other ions, protons (H(+)) and hydroxide ions (OH(-)) exhibit anomalously high mobilities in aqueous solutions. On a qualitative level, this behaviour has long been explained by 'structural diffusion' the continuous interconversion between hydration complexes driven by fluctuations in the solvation shell of the hydrated ions. Detailed investigations have led to a clear understanding of the proton transport mechanism at the molecular level. In contrast, hydroxide ion mobility in basic solutions has received far less attention, even though bases and base catalysis play important roles in many organic and biochemical reactions and in the chemical industry. The reason for this may be attributed to the century-old notion that a hydrated OH(-) can be regarded as a water molecule missing a proton, and that the transport mechanism of such a 'proton hole' can be inferred from that of an excess proton by simply reversing hydrogen bond polarities. However, recent studies have identified OH(-) hydration complexes that bear little structural similarity to proton hydration complexes. Here we report the solution structures and transport mechanisms of hydrated hydroxide, which we obtained from first-principles computer simulations that explicitly treat quantum and thermal fluctuations of all nuclei. We find that the transport mechanism, which differs significantly from the proton hole picture, involves an interplay between the previously identified hydration complexes and is strongly influenced by nuclear quantum effects.

Journal Article↗

PubMed2002

Using novel variable transformations to enhance conformational sampling in molecular dynamics.

One of the computational "grand challenges" is to develop methodology capable of sampling conformational equilibria in systems with rough energy landscapes. Here, a significant step forward is made by combining molecular dynamics with a novel variable transformation designed to enhance sampling by reducing barriers without introducing bias and, thus, to preserve, perfectly, equilibrium properties.

Models, Chemical↗