Semiempirical Quantum Mechanical Methods for Noncovalent Interactions for Chemical and Biochemical Applications

Christensen, Anders S.; Kubař, Tomáš; Cui, Qiang; Elstner, Marcus

doi:10.1021/acs.chemrev.5b00584

Cited by 346 publications

(421 citation statements)

References 327 publications

(734 reference statements)

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“…Rather, it is an additional contribution to the forces acting at short distance that can enhance the affinity and are intrinsically enantioselective. It has long been known that the current physical models used to describe the interaction between biological molecules do not properly account for the enantioselectivity and binding energies in biorecognition (2)(3)(4)(5). In the past, this gap was filled using empirically based methods (34).…”

Section: Discussionmentioning

confidence: 99%

“…Biorecognition, which is based on noncovalent interactions between molecules, retains mysteries, and its calculation evades first principles theory (2, 3). This failure suggests that some essential features are not included in our current description of these interactions (4,5). In this study, we show that charge polarization, which occurs in any biorecognition event, is accompanied by spin polarization for chiral molecules, an effect that is missing in most treatments.…”

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confidence: 83%

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Chirality-induced spin polarization places symmetry constraints on biomolecular interactions

Kumar

Capua

Kesharwani

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

171

236

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Noncovalent interactions between molecules are key for many biological processes. Necessarily, when molecules interact, the electronic charge in each of them is redistributed. Here, we show experimentally that, in chiral molecules, charge redistribution is accompanied by spin polarization. We describe how this spin polarization adds an enantioselective term to the forces, so that homochiral interaction energies differ from heterochiral ones. The spin polarization was measured by using a modified Hall effect device. An electric field that is applied along the molecules causes charge redistribution, and for chiral molecules, a Hall voltage is measured that indicates the spin polarization. Based on this observation, we conjecture that the spin polarization enforces symmetry constraints on the biorecognition process between two chiral molecules, and we describe how these constraints can lead to selectivity in the interaction between enantiomers based on their handedness. Model quantum chemistry calculations that rigorously enforce these constraints show that the interaction energy for methyl groups on homochiral molecules differs significantly from that found for heterochiral molecules at van der Waals contact and shorter (i.e., ∼0.5 kcal/mol at 0.26 nm).spin | chirality | enantioselectivity | biorecognition | exchange interaction T he wealth of information on protein structure has led to a much better understanding of the relation between structure and function in biomolecular processes and biological machines (1); however, basic phenomena remain unexplained in terms of structure-function relationships. Biorecognition, which is based on noncovalent interactions between molecules, retains mysteries, and its calculation evades first principles theory (2, 3). This failure suggests that some essential features are not included in our current description of these interactions (4,5). In this study, we show that charge polarization, which occurs in any biorecognition event, is accompanied by spin polarization for chiral molecules, an effect that is missing in most treatments. The subsequent magnetic interaction energies are small and therefore, play no significant role in the interactions; however, the spin polarization constrains the symmetry of the wave function(s) involved with the intermolecular interaction, so that significant differences in energy emerge for interactions between molecules of the same chirality and those of opposite chirality. Thus, this phenomenon may impact quantitative modeling of biorecognition events and contribute to our understanding of enantiorecognition in nature (6).Nucleotides, amino acids, and sugars are chiral; namely, they do not possess mirror plane symmetry but have symmetry like a "hand" (cheir in Greek). Force field models for the interaction between biomolecules do not account for spin polarization or include terms with chiral symmetry. Noncovalent interactions between biomolecules are commonly described classically by way of force fields, which are constructed from their geometrie...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 83%

Chirality-induced spin polarization places symmetry constraints on biomolecular interactions

Kumar

Capua

Kesharwani

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

171

236

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“…59 For metalloenzyme applications, recent DFTB3 developments have led to encouraging results in predicting structural and semi-quantitative energetic properties, 75–77 including trends in phosphoryl transfer transition state properties in alkaline phosphatase. 63,64 Nevertheless, we perform calibration for DFTB3/3OB-OPhyd 61 using B3LYP calculations for both model and enzyme systems (see Supporting Information); although there remain quantitative errors in DFTB3/3OB-OPhyd, the results support the general trends observed in the DFTB3/CHARMM simulations since the errors are systematic.…”

Section: Methodsmentioning

confidence: 99%

Regulation and Plasticity of Catalysis in Enzymes: Insights from Analysis of Mechanochemical Coupling in Myosin

et al. 2017

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The mechanism of ATP hydrolysis in the myosin motor domain is analyzed using a combination of DFTB3/CHARMM simulations and enhanced sampling techniques. The motor domain is modeled in the pre-powerstroke state, in the post-rigor state, and a hybrid model based on the post-rigor state with a closed nucleotide-binding pocket. The ATP hydrolysis activity is found to depend on the positioning of nearby water molecules, and a network of polar residues facilitates proton transfer and charge redistribution during hydrolysis. Comparison of the observed hydrolysis pathways and the corresponding free energy profiles leads to detailed models for the mechanism of ATP hydrolysis in the pre-powerstroke state and proposes factors that regulate the hydrolysis activity in different conformational states. In the pre-powerstroke state, the scissile Pγ-O3β bond breaks early in the reaction. Proton transfer from the lytic water to the γ-phosphate through active site residues is an important part of the kinetic bottleneck; several hydrolysis pathways that feature distinct proton transfer routes are found to have similar free energy barriers, suggesting a significant degree of plasticity in the hydrolysis mechanism. Comparison of hydrolysis in the pre-powerstroke state and the closed post-rigor model suggests that optimization of residues beyond the active site for electrostatic stabilization and pre-organization is likely important to enzyme design.

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“…using a reaction force field for the case involving chemical reactions, may give rise to a set of rotamers fit for this purpose. In addition, backbone conformations associated with loop motions and large domain (secondary or tertiary structures) movement [124], might also be modeled in this way, and complemented using mode vibrations simulations from QM, hybrid QM/MM, or semi-empirical QM methods [125]. …”

Section: Challenges In Automated Protein Designmentioning

confidence: 99%

Recent advances in automated protein design and its future challenges

Setiawan

Brender

Zhang

2018

Expert Opinion on Drug Discovery

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Introduction Protein function is determined by protein structure which is in turn determined by the corresponding protein sequence. If the rules that cause a protein to adopt a particular structure are understood, it should be possible to refine or even redefine the function of a protein by working backwards from the desired structure to the sequence. Automated protein design attempts to calculate the effects of mutations computationally with the goal of more radical or complex transformations than are accessible by experimental techniques. Areas covered The authors give a brief overview of the recent methodological advances in computer-aided protein design, showing how methodological choices affect final design and how automated protein design can be used to address problems considered beyond traditional protein engineering, including the creation of novel protein scaffolds for drug development. Also, the authors address specifically the future challenges in the development of automated protein design. Expert opinion Automated protein design holds potential as a protein engineering technique, particularly in cases where screening by combinatorial mutagenesis is problematic. Considering solubility and immunogenicity issues, automated protein design is initially more likely to make an impact as a research tool for exploring basic biology in drug discovery than in the design of protein biologics.

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Semiempirical Quantum Mechanical Methods for Noncovalent Interactions for Chemical and Biochemical Applications

Cited by 346 publications

References 327 publications

Chirality-induced spin polarization places symmetry constraints on biomolecular interactions

Chirality-induced spin polarization places symmetry constraints on biomolecular interactions

Regulation and Plasticity of Catalysis in Enzymes: Insights from Analysis of Mechanochemical Coupling in Myosin

Recent advances in automated protein design and its future challenges

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