2,466 research outputs found
Exploration of Reaction Pathways and Chemical Transformation Networks
For the investigation of chemical reaction networks, the identification of
all relevant intermediates and elementary reactions is mandatory. Many
algorithmic approaches exist that perform explorations efficiently and
automatedly. These approaches differ in their application range, the level of
completeness of the exploration, as well as the amount of heuristics and human
intervention required. Here, we describe and compare the different approaches
based on these criteria. Future directions leveraging the strengths of chemical
heuristics, human interaction, and physical rigor are discussed.Comment: 48 pages, 4 figure
Revealing quantum mechanical effects in enzyme catalysis with large-scale electronic structure simulation
Enzymes have evolved to facilitate challenging reactions at ambient conditions with specificity seldom matched by other catalysts. Computational modeling provides valuable insight into catalytic mechanism, and the large size of enzymes mandates multi-scale, quantum mechanical-molecular mechanical (QM/MM) simulations. Although QM/MM plays an essential role in balancing simulation cost to enable sampling with the full QM treatment needed to understand electronic structure in enzyme active sites, the relative importance of these two strategies for understanding enzyme mechanism is not well known. We explore challenges in QM/MM for studying the reactivity and stability of three diverse enzymes: i) Mg[supercript 2+]-dependent catechol O-methyltransferase (COMT), ii) radical enzyme choline trimethylamine lyase (CutC), and iii) DNA methyltransferase (DNMT1), which has structural Zn[superscript 2+] binding sites. In COMT, strong non-covalent interactions lead to long range coupling of electronic structure properties across the active site, but the more isolated nature of the metallocofactor in DNMT1 leads to faster convergence of some properties. We quantify these effects in COMT by computing covariance matrices of by-residue electronic structure properties during dynamics and along the reaction coordinate. In CutC, we observe spontaneous bond cleavage following initiation events, highlighting the importance of sampling and dynamics. We use electronic structure analysis to quantify the relative importance of CHO and OHO non-covalent interactions in imparting reactivity. These three diverse cases enable us to provide some general recommendations regarding QM/MM simulation of enzymes.NEC CorporationNational Institute of Environmental Health Sciences (Grant P30-ES002109)Burroughs Wellcome Fund (Career Award at the Scientific Interface)United States. Department of Energy (Computational Science Graduate Fellowship
Automated exploration of prebiotic chemical reaction space: progress and perspectives
Prebiotic chemistry often involves the study of complex systems of chemical reactions that form large networks with a large number of diverse species. Such complex systems may have given rise to emergent phenomena that ultimately led to the origin of life on Earth. The environmental conditions and processes involved in this emergence may not be fully recapitulable, making it difficult for experimentalists to study prebiotic systems in laboratory simulations. Computational chemistry offers efficient ways to study such chemical systems and identify the ones most likely to display complex properties associated with life. Here, we review tools and techniques for modelling prebiotic chemical reaction networks and outline possible ways to identify self-replicating features that are central to many origin-of-life models
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Understanding the Mechanism of Human P450 CYP1A2 Using Coupled Quantum-Classical Simulations in a Dynamical Environment
The reaction mechanism of the human P450 CYP1A2 enzyme plays a fundamental role in understanding the effects of environmental carcinogens and mutagens on humans. Despite extensive experimental research on this enzyme system, key questions regarding its catalytic cycle and oxygen activation mechanism remain unanswered. In order to elucidate the reaction mechanism in human P450, new computational methods are needed to accurately represent this system. To enable us to perform computational simulations of unprecedented accuracy on these systems, we developed a dynamic quantum-classical (QM/MM) hybrid method, in which ab initio molecular dynamics are coupled with classical molecular mechanics. This will provide the accuracy needed to address such a complex, large biological system in a fully dynamic environment. We also present detailed calculations of the P450 active site, including the relative charge transfer between iron porphine and tetraphenyl porphyrin
A Computational perspective on the concerted cleavage mechanism of the natural targets of HIV-1 protease.
Doctoral Degree. University of KwaZulu-Natal, Durban.One infectious disease that has had both a profound health and cultural impact on the human race
in recent decades is the Acquired Immune Deficiency Syndrome (AIDS) caused by the Human
Immunodeficiency Virus (HIV). A major breakthrough in the treatment of HIV-1 was the use of
drugs inhibiting specific enzymes necessary for the replication of the virus. Among these
enzymes is HIV-1 protease (PR), which is an important degrading enzyme necessary for the
proteolytic cleavage of the Gag and Gag-Pol polyproteins, required for the development of
mature virion proteins. The mechanism of action of the HIV-1 PR on the proteolysis of these
polyproteins has been a subject of research over the past three decades.
Most investigations on this subject have been dedicated to exploring the reaction mechanism of
HIV-1 PR on its targets as a stepwise general acid-base process with little attention on a
concerted model. One of the shortcomings of the stepwise reaction pathway is the existence of
more than two TS moieties, which have led to varying opinions on the exact rate-determining
step of the reaction and the protonation pattern of the catalytic aspartate group at the HIV-1 PR
active site. Also, there is no consensus on the actual recognition mechanism of the natural
substrates by the HIV-1 PR.
By means of concerted transition state (TS) structural models, the recognition mode and the
reaction mechanism of HIV-1 PR with its natural targets were investigated in this present study.
The investigation was designed to elucidate the cleavage of natural substrates by HIV-1 PR using
the concerted TS model through the application of computational methods to unravel the
recognition and reaction process, compute activation parameters and elucidate quantum chemical
properties of the system.
Quantum mechanics (QM) methods including the density functional theory (DFT) models and
Hartree-Fock (HF), molecular mechanics (MM) and hybrid QM/MM were employed to provide
better insight in this topic. Based on experience with concerted TS modelling, the six-membered
ring TS structure was proposed. Using a small model system and QM methods (DFT and HF),
the enzymatic mechanism of HIV-1 PR was studied as a general acid-base model having both
catalytic aspartate group participating and water molecule attacking the natural substrate
synchronously. The natural substrate scissile bond strength was also investigated via changes of
electronic effects. The proposed concerted six-membered ring TS mechanism of the natural
substrate within the entire enzyme was studied using hybrid QM/MM; “Our own N-layered Integrated molecular Orbital and molecular Mechanics” (ONIOM) method. This investigation
led us to a new perspective in which an acyclic concerted pathway provided a better approach to
the subject than the proposed six-membered model. The natural substrate recognition pattern
was therefore investigated using the concerted acyclic TS modelling to examine if HIV-1 (South
Africa subtype C, C-SA and subtype B) PRs recognize their substrates in the same manner using
ONIOM approach.
A major outcome in the present investigation is the computational modelling of a new,
potentially active, substrate-based inhibitor through the six-membered concerted cyclic TS
modelling and a small system. By modelling the entire enzyme—substrate system using a
hybrid QM/MM (ONIOM) method, three different pathways were obtained. (1) A concerted
acyclic TS structure, (2) a concerted six-membered cyclic TS model and (3) another sixmembered
ring TS model involving two water molecules. The activation free energies obtained
for the first and the last pathways were in agreement with in vitro HIV-1 PR hydrolysis data.
The mechanism that provides marginally the lowest activation barrier involves an acyclic TS
model with one water molecule at the HIV-1 PR active site. The outcome of the study provides
a plausible theoretical benchmark for the concerted enzymatic mechanism of HIV-1 PRs which
could be applied to related homodimeric protease and perhaps other enzymatic processes.
Applying the one-step concerted acyclic catalytic mechanism for two HIV-1 PR subtypes, the
recognition phenomena of both enzyme and substrate were studied. It was observed that the
studied HIV-1 PR subtypes (B and C-SA) recognize and cleave at both scissile and non-scissile
regions of the natural substrate sequences and maintaining preferential specificity for the scissile
bonds with characteristic lower activation free energies.
Future studies on the reaction mechanism of HIV-1 PR and natural substrates should involve the
application of advanced computational techniques to provide plausible answers to some
unresolved perspectives. Theoretical investigations on the enzymatic mechanism of HIV-1 PR—
natural substrate in years to come, would likely involve the application of sophisticated
computational techniques aimed at exploring more than the energetics of the system. The
possibility of integrated computational algorithms which do not involve
partitioning/restraining/constraining/cropped model systems of the enzyme—substrate
mechanism would likely surface in future to accurately elucidate the HIV-1 PR catalytic process on natural substrates/ligands
Perturbatively corrected ring-polymer instanton theory for accurate tunneling splittings
We introduce an approach for calculating perturbative corrections to the
ring-polymer instanton approximation to tunneling splittings (RPI+PC), by
computing higher-order terms in the asymptotic expansion in . The
resulting method goes beyond standard instanton theory by using information on
the third and fourth derivatives of the potential along the tunneling path to
include additional anharmonic effects. This leads to significant improvements
both in systems with low barriers and in systems with anharmonic modes. We
demonstrate the applicability of RPI+PC to molecular systems by computing the
tunneling splitting in full-dimensional malonaldehyde and a deuterated
derivative. Comparing to both experiment and recent quantum-mechanical
benchmark results, we find that our perturbative correction reduces the error
from -11% to 2% for hydrogen transfer and performs even better for the
deuterated case. This makes our approach more accurate than previous
calculations using diffusion Monte Carlo and path-integral molecular dynamics,
while being more computationally efficient.Comment: 18 pages, 4 figure
CHARMM: The biomolecular simulation program
CHARMM (Chemistry at HARvard Molecular Mechanics) is a highly versatile and widely used molecular simulation program. It has been developed over the last three decades with a primary focus on molecules of biological interest, including proteins, peptides, lipids, nucleic acids, carbohydrates, and small molecule ligands, as they occur in solution, crystals, and membrane environments. For the study of such systems, the program provides a large suite of computational tools that include numerous conformational and path sampling methods, free energy estimators, molecular minimization, dynamics, and analysis techniques, and model-building capabilities. The CHARMM program is applicable to problems involving a much broader class of many-particle systems. Calculations with CHARMM can be performed using a number of different energy functions and models, from mixed quantum mechanical-molecular mechanical force fields, to all-atom classical potential energy functions with explicit solvent and various boundary conditions, to implicit solvent and membrane models. The program has been ported to numerous platforms in both serial and parallel architectures. This article provides an overview of the program as it exists today with an emphasis on developments since the publication of the original CHARMM article in 1983. © 2009 Wiley Periodicals, Inc.J Comput Chem, 2009.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63074/1/21287_ftp.pd
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