16 research outputs found
Projected Hybrid Orbitals: A General QM/MM Method
A projected hybrid orbital (PHO)
method was described to model
the covalent boundary in a hybrid quantum mechanical and molecular
mechanical (QM/MM) system. The PHO approach can be used in ab initio
wave function theory and in density functional theory with any basis
set without introducing system-dependent parameters. In this method,
a secondary basis set on the boundary atom is introduced to formulate
a set of hybrid atomic orbtials. The primary basis set on the boundary
atom used for the QM subsystem is projected onto the secondary basis
to yield a representation that provides a good approximation to the
electron-withdrawing power of the primary basis set to balance electronic
interactions between QM and MM subsystems. The PHO method has been
tested on a range of molecules and properties. Comparison with results
obtained from QM calculations on the entire system shows that the
present PHO method is a robust and balanced QM/MM scheme that preserves
the structural and electronic properties of the QM region
AM1/d-CB1: A Semiempirical Model for QM/MM Simulations of Chemical Glycobiology Systems
A semiempirical method based on the
AM1/d Hamiltonian is introduced
to model chemical glycobiological systems. We included in the parameter
training set glycans and the chemical environment often found about
them in glycoenzymes. Starting with RM1 and AM1/d-PhoT models we optimized
H, C, N, O, and P atomic parameters targeting the best performing
molecular properties that contribute to enzyme catalyzed glycan reaction
mechanisms. The training set comprising glycans, amino acids, phosphates
and small organic model systems was used to derive parameters that
reproduce experimental data or high-level density functional results
for carbohydrate, phosphate and amino acid heats of formation, amino
acid proton affinities, amino acid and monosaccharide dipole moments,
amino acid ionization potentials, water-phosphate interaction energies,
and carbohydrate ring pucker relaxation times. The result is the AM1/d-Chemical
Biology 1 or AM1/d-CB1 model that is considerably more accurate than
existing NDDO methods modeling carbohydrates and the amino acids often
present in the catalytic domains of glycoenzymes as well as the binding
sites of lectins. Moreover, AM1/d-CB1 computed proton affinities,
dipole moments, ionization potentials and heats of formation for transition
state puckered carbohydrate ring conformations, observed along glycoenzyme
catalyzed reaction paths, are close to values computed using DFT M06-2X.
AM1/d-CB1 provides a platform from which to accurately model reactions
important in chemical glycobiology
Spin-Multiplet Components and Energy Splittings by Multistate Density Functional Theory
Kohn–Sham
density functional theory has been tremendously
successful in chemistry and physics. Yet, it is unable to describe
the energy degeneracy of spin-multiplet components with any approximate
functional. This work features two contributions. (1) We present a
multistate density functional theory (MSDFT) to represent spin-multiplet
components and to determine multiplet energies. MSDFT is a hybrid
approach, taking advantage of both wave function theory and density
functional theory. Thus, the wave functions, electron densities and
energy density-functionals for ground and excited states and for different
components are treated on the same footing. The method is illustrated
on valence excitations of atoms and molecules. (2) Importantly, a
key result is that for cases in which the high-spin components can
be determined separately by Kohn–Sham density functional theory,
the transition density functional in MSDFT (which describes electronic
coupling) can be defined rigorously. The numerical results may be
explored to design and optimize transition density functionals for
configuration coupling in multiconfigurational DFT
Beyond Kohn–Sham Approximation: Hybrid Multistate Wave Function and Density Functional Theory
A multistate density
functional theory (MSDFT) is presented in
which the energies and densities for the ground and excited states
are treated on the same footing using multiconfigurational approaches.
The method can be applied to systems with strong correlation and to
correctly describe the dimensionality of the conical intersections
between strongly coupled dissociative potential energy surfaces. A
dynamic-then-static framework for treating electron correlation is
developed to first incorporate dynamic correlation into contracted
state functions through block-localized Kohn–Sham density functional
theory (KSDFT), followed by diagonalization of the effective Hamiltonian
to include static correlation. MSDFT can be regarded as a hybrid of
wave function and density functional theory. The method is built on
and makes use of the current approximate density functional developed
in KSDFT, yet it retains its computational efficiency to treat strongly
correlated systems that are problematic for KSDFT but too large for
accurate WFT. The results presented in this work show that MSDFT can
be applied to photochemical processes involving conical intersections
Connecting Protein Conformational Dynamics with Catalytic Function As Illustrated in Dihydrofolate Reductase
Combined quantum mechanics/molecular mechanics molecular
dynamics simulations reveal that the M20 loop conformational dynamics
of dihydrofolate reductase (DHFR) is severely restricted at the transition
state of the hydride transfer as a result of the M42W/G121V double
mutation. Consequently, the double-mutant enzyme has a reduced entropy
of activation, i.e., increased entropic barrier, and altered temperature
dependence of kinetic isotope effects in comparison with those of
wild-type DHFR. Interestingly, in both wild-type DHFR and the double
mutant, the average donor–acceptor distances are essentially
the same in the Michaelis complex state (∼3.5 Å) and the
transition state (2.7 Ã…). It was found that an additional hydrogen
bond is formed to stabilize the M20 loop in the closed conformation
in the M42W/G121V double mutant. The computational results reflect
a similar aim designed to knock out precisely the dynamic flexibility
of the M20 loop in a different double mutant, N23PP/S148A
Chemical Control in the Battle against Fidelity in Promiscuous Natural Product Biosynthesis: The Case of Trichodiene Synthase
Terpene cyclases catalyze the highly
stereospecific molding of polyisoprenes into terpenes, which are precursors
to most known natural compounds. The isoprenoids are formed via intricate
chemical cascades employing rich, yet highly erratic, carbocation
chemistry. It is currently not well understood how these biocatalysts
achieve chemical control. Here, we illustrate the catalytic control
exerted by trichodiene synthase, and in particular, we discover two
features that could be general catalytic tools adopted by other terpenoid
cyclases. First, to avoid formation of byproducts, the enzyme raises the energy
of bisabolyl carbocation, which is a general mechanistic branching
point in many sesquiterpene cyclases, resulting in an essentially
concerted cyclization cascade. Second, we identify a sulfur–carbocation
dative bonding interaction that anchors the bisabolyl cation in a reactive conformation,
avoiding tumbling and premature deprotonation. Specifically, Met73
acts as a chameleon, shifting from an initial sulfur−π
interaction in the Michaelis complex to a sulfur–carbocation
complex during catalysis
Diabatic-At-Construction Method for Diabatic and Adiabatic Ground and Excited States Based on Multistate Density Functional Theory
We
describe a diabatic-at-construction (DAC) strategy for defining
diabatic states to determine the adiabatic ground and excited electronic
states and their potential energy surfaces using the multistate density
functional theory (MSDFT). The DAC approach differs in two fundamental
ways from the adiabatic-to-diabatic (ATD) procedures that transform
a set of preselected adiabatic electronic states to a new representation.
(1) The DAC states are defined in the first computation step to form
an active space, whose configuration interaction produces the adiabatic
ground and excited states in the second step of MSDFT. Thus, they
do not result from a similarity transformation of the adiabatic states
as in the ATD procedure; they are the basis for producing the adiabatic
states. The appropriateness and completeness of the DAC active space
can be validated by comparison with experimental observables of the
ground and excited states. (2) The DAC diabatic states are defined
using the valence bond characters of the asymptotic dissociation limits
of the adiabatic states of interest, and they are strictly maintained
at all molecular geometries. Consequently, DAC diabatic states have
specific and well-defined physical and chemical meanings that can
be used for understanding the nature of the adiabatic states and their
energetic components. Here we present results for the four lowest
singlet states of LiH and compare them to a well-tested ATD diabatization
method, namely the 3-fold way; the comparison reveals both similarities
and differences between the ATD diabatic states and the orthogonalized
DAC diabatic states. Furthermore, MSDFT can provide a quantitative
description of the ground and excited states for LiH with multiple
strongly and weakly avoided curve crossings spanning over 10 Ã…
of interatomic separation
Multistate Density Functional Theory for Effective Diabatic Electronic Coupling
Multistate density functional theory
(MSDFT) is presented to estimate
the effective transfer integral associated with electron and hole
transfer reactions. In this approach, the charge-localized diabatic
states are defined by block localization of Kohn–Sham orbitals,
which constrain the electron density for each diabatic state in orbital
space. This differs from the procedure used in constrained density
functional theory that partitions the density within specific spatial
regions. For a series of model systems, the computed transfer integrals
are consistent with experimental data and show the expected exponential
attenuation with the donor–acceptor separation. The present
method can be used to model charge transfer reactions including processes
involving coupled electron and proton transfer
Perturbation Approach for Computing Infrared Spectra of the Local Mode of Probe Molecules
Linear
and two-dimensional infrared (IR) spectroscopy of site-specific
probe molecules provides an opportunity to gain a molecular-level
understanding of the local hydrogen-bonding network, conformational
dynamics, and long-range electrostatic interactions in condensed-phase
and biological systems. A challenge in computation is to determine
the time-dependent vibrational frequencies that incorporate explicitly
both nuclear quantum effects of vibrational motions and an electronic
structural representation of the potential energy surface. In this
paper, a nuclear quantum vibrational perturbation (QVP) method is
described for efficiently determining the instantaneous vibrational
frequency of a chromophore in molecular dynamics simulations. Computational
efficiency is achieved through the use of (a) discrete variable representation
of the vibrational wave functions, (b) a perturbation theory to evaluate
the vibrational energy shifts due to solvent dynamic fluctuations,
and (c) a combined QM/MM potential for the systems. It was found that
first-order perturbation is sufficiently accurate, enabling time-dependent
vibrational frequencies to be obtained on the fly in molecular dynamics.
The QVP method is illustrated in the mode-specific linear and 2D-IR
spectra of the H–Cl stretching frequency in the HCl–water
clusters and the carbonyl stretching vibration of acetone in aqueous
solution. To further reduce computational cost, a hybrid strategy
was proposed, and it was found that the computed vibrational spectral
peak position and line shape are in agreement with experimental results.
In addition, it was found that anharmonicity is significant in the
H–Cl stretching mode, and hydrogen-bonding interactions further
enhance anharmonic effects. The present QVP method complements other
computational approaches, including path integral-based molecular
dynamics, and represents a major improvement over the electrostatics-based
spectroscopic mapping procedures
Conformational Equilibrium of N‑Myristoylated cAMP-Dependent Protein Kinase A by Molecular Dynamics Simulations
The catalytic subunit of protein kinase A (PKA-C) is
subject to
several post- or cotranslational modifications that regulate its activity
both spatially and temporally. Among those, N-myristoylation increases
the kinase affinity for membranes and might also be implicated in
substrate recognition and allosteric regulation. Here, we investigated
the effects of N-myristoylation on the structure, dynamics, and conformational
equilibrium of PKA-C using atomistic molecular dynamics simulations.
We found that the myristoyl group inserts into the hydrophobic pocket
and leads to a tighter packing of the A-helix against the core of
the enzyme. As a result, the conformational dynamics of the A-helix
are reduced and its motions are more coupled with the active site.
Our simulations suggest that cation−π interactions among
W30, R190, and R93 are responsible for coupling these motions. Two
major conformations of the myristoylated N-terminus are the most populated:
a long loop (LL conformation), similar to Protein Data Bank (PDB)
entry 1CMK,
and a helix–turn–helix structure (HTH conformation),
similar to PDB entry 4DFX, which shows stronger coupling between the conformational dynamics
observed at the A-helix and active site. The HTH conformation is stabilized
by S10 phosphorylation of the kinase via ionic interactions between
the protonated amine of K7 and the phosphate group on S10, further
enhancing the dynamic coupling to the active site. These results support
a role of N-myristoylation in the allosteric regulation of PKA-C