29 research outputs found
Efficient Conformational Search Based on Structural Dissimilarity Sampling: Applications for Reproducing Structural Transitions of Proteins
Structural Dissimilarity Sampling
(SDS) is proposed as an efficient
conformational search method to promote structural transitions essential
for the biological functions of proteins. In SDS, initial structures
are selected based on structural dissimilarity, and conformational
resampling is repeated. Conformational resampling is performed as
follows: (I) arrangement of initial structures for a diverse distribution
at the edge of a conformational subspace and (II) promotion of the
structural transitions with multiple short-time molecular dynamics
(MD) simulations restarting from the diversely distributed initial
structures. Cycles of (I) and (II) are repeated to intensively promote
structural transitions because conformational resampling from the
initial structures would quickly expand conformational distributions
toward unvisited conformational subspaces. As a demonstration, SDS
was first applied to maltodextrin binding protein (MBP) in explicit
water to reproduce structural transitions between the open and closed
states of MBP. Structural transitions of MBP were successfully reproduced
with SDS in nanosecond-order simulation times. Starting from both
the open and closed forms, SDS successfully reproduced the structural
transitions within 25 cycles (a total of 250 ns of simulation time).
For reference, a conventional long-time (500 ns) MD simulation under <i>NPT</i> (300 K and 1 bar) starting from the open form failed
to reproduce the structural transition. In addition to the open–closed
motions of MBP, SDS was applied to folding processes of the fast-folding
proteins (chignolin, Trp-cage, and villin) and successfully sampled
their native states. To confirm how the selections of initial structures
affected conformational sampling efficiency, numbers of base sets
for characterizing structural dissimilarity of initial structures
were addressed in distinct trials of SDS. The parameter searches showed
that the conformational sampling efficiency was relatively insensitive
with respect to the numbers of base sets, indicating the robustness
of SDS for actual applications
Temperature-Shuffled Structural Dissimilarity Sampling Based on a Root-Mean-Square Deviation
Structural
dissimilarity sampling (SDS) has been proposed as an
enhanced conformational sampling method for finding neighboring metastable
states of a given reactant or generating transition pathways starting
from the reactant. SDS repeats a cycle of two steps: (1) selections
of initial structures based on structural dissimilarities by referring
to a measure and (2) conformational resampling by restarting short-time
molecular dynamics (MD) simulations from the initial structures. In
the present study, the measure was defined as the root-mean-square
deviation (RMSD) among the resampled snapshots to characterize their
structural dissimilarities. Additionally, the temperatures in restarting
the short-time MD simulations were randomly shuffled at the beginning
of each cycle to further promote the conformational transitions. We
call this approach temperature-shuffled SDS (TSF-SDS). As a demonstration,
TSF-SDS was applied to promote the open–closed transition of
T4 lysozyme (T4L) in explicit water. TSF-SDS successfully reproduced
the relevant domain motion with nanosecond-order simulation time,
whereas conventional SDS without shuffling of the temperatures failed
to promote the transition of T4L, indicating the high conformational
sampling efficiency of TSF-SDS for promoting essential conformational
transitions of proteins. Furthermore, as a wide-range application,
TSF-SDS efficiently identified the native state of trp-cage and a
dissociation process of ubiquitin dimer in explicit water
Self-Avoiding Conformational Sampling Based on Histories of Past Conformational Searches
Self-avoiding
conformational sampling (SACS) is proposed as an
enhanced conformational sampling method for proteins. In SACS, the
following conformational resampling is repeated for a given protein:
(1) identification of newly visited states in a subspace and (2) conformational
resampling by restarting short-time molecular dynamics (MD) simulations
from the newly visited states. To identify the newly visited states,
a set of history-dependent histograms projected onto the subspace
is used. One is constructed from the trajectories sampled at the current
(<i>i</i>th) cycle, and the other is constructed from all
of the trajectories accumulated up through the previous ((<i>i</i> – 1)Âth) cycle. By reference to the history-dependent
histograms, the newly visited states appearing at the current (<i>i</i>th) cycle are defined as a difference set between them.
By repeating the cycle of conformational resampling, SACS prevents
the system from revisiting states that have already been visited for
previous cycles, promoting structural transitions via resampling from
the newly visited states. To verify the conformational sampling efficiency
of SACS, the present method was applied to reveal underlying mechanisms
of biologically important domain motions of maltodextrin binding protein
in explicit water and successfully reproduced the open–closed
transition with a reasonable (nanosecond-order) computational cost
Assessment of Methodology and Chemical Group Dependences in the Calculation of the p<i>K</i><sub>a</sub> for Several Chemical Groups
We have investigated the dependencies
of various computational
methods in the calculation of acid dissociation constants (p<i>K</i><sub>a</sub> values) of certain chemical groups found in
protonatable amino acids based on our previous scheme [Matsui; Phys. Chem. Chem. Phys. 2012, 14, 4181−4187]. By changing the quantum chemical (QC) method (Hartree–Fock
(HF) and perturbation theory, and composite methods, or exchange–correlation
functionals in density functional theory (DFT)), basis sets, solvation
models, and the cavities used in the solvent models, we have exhaustively
tested about 2,200 combinations to find the best combination for p<i>K</i><sub>a</sub> estimation among them. Of the tested parameters,
the choice of the basis set and cavity is the most crucial to reproduce
experimental values compared to other factors. Concerning the basis
set, the inclusion of diffuse functions is quite important for carboxyl,
thiol, and phenol groups judging from the mean absolute errors (MAEs)
measured from the experimental values. Of the cavity models, between
the Pauling, Klamt, and the universal force field (UFF) definitions,
the UFF defined cavity is the best choice, resulting in the smallest
MAEs. Concerning the QC methods, hybrid DFTs and range-separated DFTs
always provide better results than pure DFTs and HF. As a result,
we found that LC-Ï–PBE/6-31+GÂ(d) with PCM-SMD/UFF provides the
best p<i>K</i><sub>a</sub> estimation with a MAE within
0.15 p<i>K</i><sub>a</sub> units
Ion-Pairing Crystal Polymorphs of Interlocked [2 + 1]-Type Receptor–Anion Complexes
The formation of
a solid-state totally charge-segregated assembly
(polymorph <b>A</b>) of negatively charged layers comprising
[2 + 1]-type Cl<sup>–</sup> complexes of an arylethynyl-substituted
dipyrrolyldiketone boron complex and positively charged layers of
tetrabutylammonium (TBA) cations has already been reported. The formation
of two new crystalline polymorphs (polymorphs <b>B</b> and <b>C</b>), in addition to polymorph <b>A</b>, is reported in
this study. Both polymorphs <b>B</b> and <b>C</b> formed
charge-by-charge assemblies, and the dihedral angles between two receptor
units in the interlocked complexes depended on the geometries of TBA
cations and the resulting packing structures. Two nonorthogonally
arranged planes induced <i>P</i>- and <i>M</i>-form chiral geometries, providing diverse arrangements of chiral
species according to crystal polymorphs. Furthermore, the stabilities
of the three polymorphs were examined by interfragment interaction
energies, which were calculated by <i>ab initio</i> electronic
structure calculations using the fragment molecular orbital (FMO)
method
Theoretical Insight into Stereoselective Reaction Mechanisms of 2,4-Pentanediol-Tethered Ketene-Olefin [2 + 2] Cycloaddition
We report ab initio molecular dynamics calculations based
on density
functional theory performed on an intramolecular [2 + 2] cycloaddition
between ketene and olefin linked with a 2,4-pentanediol (PD) tether.
We find that the encounter of the ketene and olefin moieties could
be prearranged in the thermal equilibrated state before the cycloaddition.
The reaction mechanism is found to be stepwise, similar to that of
intermolecular ketene [2 + 2] cycloadditions with ordinary alkenes.
A distinct feature of the reaction pathway for a major diastereoisomer
is a differential activation free energy of about 1.5 kcal/mol, including
2.8 kcal/mol as the differential activation entropy, with a transition
state consisting of a flexible nine-membered ring in the olefin-PD-ketene
moiety. This theoretical study provides a reasonable explanation for
the strict stereocontrollability of the PD-tethered ketene-olefin
cycloaddition, irrespective of reaction types or conditions
Protein Structure Validation Derives a Smart Conformational Search in a Physically Relevant Configurational Subspace
Since proteins perform biological functions through their
dynamic
properties, molecular dynamics (MD) simulation is a sophisticated
strategy for investigating their functions. Analyses of trajectories
provide statistical information about a specific protein as a free-energy
landscape (FEL). However, the timescale of normal MD is shorter than
that of biological functions, resulting in statistically insufficient
conformational sampling, finally leading to unreliable FEL calculation.
To search for a broad configurational subspace, an external bias is
imposed on a target protein as biased sampling. However, its regulation
is challenging because the optimal strength of the perturbation is
unknown. Furthermore, a physically irrelevant configurational subspace
was searched when imposing an inappropriate external bias. To address
this issue, we newly proposed an external biased regulation scheme
known as the G-factor external bias limiter (GERBIL). In GERBIL, protein
configurations generated by external bias are structurally validated
by an indicator (G-factor), enabling the search for a physically relevant
subspace. In addition to biased sampling, nonbiased sampling might
search for a physically irrelevant configurational subspace because
repeating multiple MD simulations from several initial structures
tends to search for an overly broad configurational subspace. For
this issue, the structural qualities of configurations generated by
nonbiased sampling have not been investigated. Therefore, we confirmed
whether the G-factor screened the collapsed (low-quality) configurations
generated by nonbiased sampling. To address this issue, the outlier
flooding method (OFLOOD) was adopted in GERBIL as a nonbiased sampling
method, which is referred to as OFLOOD-GERBIL. OFLOOD rapidly expands
a configurational subspace by resampling the rarely occurring states
of a given protein and tends to search an overly broad subspace. Thus,
we considered that GERBIL might improve the excessive conformational
search of OFLOOD for a physically irrelevant configurational subspace.
As a demonstration, OFLOOD and OFLOOD-GERBIL were applied to a globular
protein (T4 lysozyme) and their conformational search qualities were
assessed. Based on our assessment, normal OFLOOD without the outlier
validation frequently sampled low-quality configurations, whereas
OFLOOD-GERBIL with the outlier validation intensively sampled high-quality
configurations. In conclusion, OFLOOD-GERBIL derives a smart conformational
search in a physically relevant configurational subspace, indicating
that protein structure validation works in both nonbiased and biased
sampling methods
A Density Functional Theory Based Protocol to Compute the Redox Potential of Transition Metal Complex with the Correction of Pseudo-Counterion: General Theory and Applications
We propose an accurate
scheme to evaluate the redox potential of
a wide variety of transition metal complexes by adding a charge-dependent
correction term for a counterion around the charged complexes, which
is based on Generalized Born theory, to the solvation energy. The
mean absolute error (MAE) toward experimental redox potentials of
charged complexes is considerably reduced from 0.81 V (maximum error
1.22 V) to 0.22 V (maximum error 0.50 V). We found a remarkable exchange-correlation
functional dependence on the results rather than the basis set ones.
The combination of Wachters+f (for metal) and 6-31++GÂ(d,p) (for other
atoms) with the B3LYP functional gives the least MAE 0.15 V for the
test complexes. This scheme is applicable to other solvents, and heavier
transition metal complexes such as M<sub>1</sub>(CO)<sub>5</sub>(pycn)
(M<sub>1</sub> = Cr, Mo, W), M<sub>2</sub>(mnt)<sub>2</sub> (M<sub>2</sub> = Ni, Pd, Pt), and M<sub>3</sub>(bpy)<sub>3</sub> (M<sub>3</sub> = Fe, Ru, Os) with the same quality
Photochromic Switching of Diradical Character: Design of Efficient Nonlinear Optical Switches
Open-shell singlet diradical molecules
have been widely investigated
because they are key to understanding the nature of chemical bonds.
We propose a new concept for reversible switching of diradical characterî—¸an
index of the instability of chemical bondsî—¸of a molecule by
photochromic reaction. Photochromic diarylethene derivatives with
various open-shell singlet diradical characters are theoretically
designed, and their photochromic diradical character switching behaviors
are clarified. These results contribute to designing highly efficient
third-order nonlinear optical switching substances based on the correlation
between the diradical character and second hyperpolarizability
Origin of the Enhancement of the Second Hyperpolarizabilities in Open-Shell Singlet Transition-Metal Systems with Metal–Metal Multiple Bonds
Using the spin-unrestricted coupled-cluster method, we explore the origin of the second hyperpolarizabilities (γ) of singlet dichromium(II) and dimolybdenum(II) model systems with various bond lengths as a function of the diradical characters of the dσ, dπ, and dδ orbitals. Both systems exhibit enhanced γ values in the intermediate diradical character region, but by using a partitioning scheme, the dσ electrons are shown to play the essential role in contrast with the π-electrons of conventional organic π-conjugated systems. Then, in the equilibrium bond length region, the γ values are still governed by dσ electrons in the dichromium(II) system, although by dδ/dπ electrons in the dimolybdenum(II) system