4 research outputs found
Assessing the Reliability of the Dynamics Reconstructed from Metadynamics
Sampling a molecular process characterized
by an activation free
energy significantly larger than <i>k</i><sub>B</sub><i>T</i> is a well-known challenge in molecular dynamics simulations.
In a recent work [Tiwary and Parrinello, <i>Phys. Rev. Lett.</i> <b>2013</b>, <i>111</i>, 230602], we have demonstrated
that the transition times of activated molecular transformations can
be computed from well-tempered metadynamics provided that no bias
is deposited in the transition state region and that the set of collective
variables chosen to enhance sampling does not display hysteresis.
Ensuring though that these two criteria are met may not always be
simple. Here we build on the fact that the times of escape from a
long-lived metastable state obey Poisson statistics. This allows us
to identify quantitative measures of trustworthiness of our calculation.
We test our method on a few paradigmatic examples
Diffusion and Aggregation of Sodium Fluorescein in Aqueous Solutions
The diffusion and aggregation of sodium fluorescein in aqueous solutions was investigated adopting density functional theory (DFT) and molecular dynamics (MD) simulations. First, DFT calculations in implicit water were used to determine minimum energy structure and atomic charges of the solute, which were then used as input for explicit water MD simulations. The self-diffusion coefficient of sodium fluorescein was calculated using the Einstein equation, computing the mean square displacement from 24 ns trajectories. The calculated diffusion coefficient, 0.42 · 10<sup>–5</sup> cm<sup>2</sup> s<sup>–1</sup>, is in good agreement with literature experimental data. The simulations confirmed the tendency of fluorescein to form dimers. In order to achieve a deeper understanding of aggregation phenomena, the dimer geometry was investigated through DFT calculations both in vacuo and in implicit water using different functionals and solvation theories. The results showed that dimerization does not occur in vacuo, as charge repulsion dominates, and that the minimum energy dimer structure is symmetric and stabilized by edge-to-face π–π interactions. The interaction energy was computed both at the DFT level and through MD simulations using Umbrella Sampling. The free interaction energy calculated with the WHAM and Umbrella Integration protocol, −1.3 kcal/mol, is in good agreement with experimental data, while the value determined using DFT calculations is significantly smaller and depends largely from the chosen functional and the computational methodology used to determine the solute–solvent boundary surface
Uncovering Molecular Details of Urea Crystal Growth in the Presence of Additives
Controlling the shape of crystals is of great practical
relevance
in fields like pharmacology and fine chemistry. Here we examine the
paradigmatic case of urea which is known to crystallize from water
with a needle-like morphology. To prevent this undesired effect, inhibitors
that selectively favor or discourage the growth of specific crystal
faces can be used. In urea the most relevant faces are the {001} and
the {110} which are known to grow fast and slow, respectively. The
relevant growth speed difference between these two crystal faces is
responsible for the needle-like structure of crystals grown in water
solution. To prevent this effect, additives are used to slow down
the growth of one face relative to another, thus controlling the shape
of the crystal. We study the growth of fast {001} and slow {110} faces
in water solution and the effect of shape controlling inhibitors like
biuret. Extensive sampling through molecular dynamics simulations
provides a microscopic picture of the growth mechanism and of the
role of the additives. We find a continuous growth mechanism on the
{001} face, while the slow growing {110} face evolves through a birth
and spread process, in which the rate-determining step is the formation
on the surface of a two-dimensional crystalline nucleus. On the {001}
face, growth inhibitors like biuret compete with urea for the adsorption
on surface lattice sites; on the {110} face instead additives cannot
interact specifically with surface sites and play a marginal sterical
hindrance of the crystal growth. The free energies of adsorption of
additives and urea are evaluated with advanced simulation methods
(well-tempered metadynamics) allowing a microscopic understanding
of the selective effect of additives. Based on this case study, general
principles for the understanding of the anisotropic growth of molecular
crystals from solutions are laid out. Our work is a step toward a
rational development of novel shape-affecting additives
Exploring the Binding Pathway of Novel Nonpeptidomimetic Plasmepsin V Inhibitors
Predicting the interaction modes
and binding affinities
of virtual
compound libraries is of great interest in drug development. It reduces
the cost and time of lead compound identification and selection. Here
we apply path-based metadynamics simulations to characterize the binding
of potential inhibitors to the Plasmodium falciparum aspartic protease plasmepsin V (plm V), a validated antimalarial
drug target that has a highly mobile binding site. The potential plm
V binders were identified in a high-throughput virtual screening (HTVS)
campaign and were experimentally verified in a fluorescence resonance
energy transfer (FRET) assay. Our simulations allowed us to estimate
compound binding energies and revealed relevant states along binding/unbinding
pathways in atomistic resolution. We believe that the method described
allows the prioritization of compounds for synthesis and enables rational
structure-based drug design for targets that undergo considerable
conformational changes upon inhibitor binding