arXiv subjects

John N. Sharley

Publications and source records attributed to John N. Sharley.

4 recordsLinked to original sources

arXiv2016

Amino acid preference against beta sheet through allowing backbone hydration enabled by the presence of cation

It is known that steric blocking by peptide sidechains of hydrogen bonding, HB, between water and peptide groups, PGs, in beta sheets accords with an amino acid intrinsic beta sheet preference. The present observations with Quantum Molecular Dynamics, QMD, simulation with quantum mechanical treatment of every water molecule solvating a beta sheet that would be transient in nature suggest that this steric blocking is not applicable in a hydrophobic region unless a cation is present, so that the amino acid beta sheet preference due to this steric blocking is only effective in the presence of a cation. We observed backbone hydration in a polyalanine and to a lesser extent polyvaline alpha helix without a cation being present, but a cation could increase the strength of these HBs. Parallel beta sheets have a greater tendency than antiparallel beta sheets of equivalent small size to retain regular structure in solvated QMD, and a 4 strand 4 inter-PG HB chain parallel beta sheet was used. Stability was reinforced by one surface being polyvaline, which buttressed the opposite surface which was used for experimentation. A single Ca2+ ion was used for investigation of individual binding events rather than bulk properties. No direct binding between Ca2+ and the PG oxygen was observed in these simulations, but perhaps it occurs at longer time scales as the transient beta sheet unfolds. When linear scaling QMD methods that are accurate for peptide resonance, Resonance-Assisted Hydrogen Bonding and the properties of water become available, more extensive experiments having multiple ions of multiple types could be performed at acceptable computational cost. It important that such investigations be performed on protein secondary structures rather than model amides so that sidechain limitation of backbone hydration and hence intrinsic amino acid propensity is captured.

physics.chem-ph↗

arXiv2016

Established DFT methods calculation of conjugation disturbed in the presence of torsional hyperconjugation

Accurate treatment of amide resonance is important in electronic structure calculation of protein, for Resonance-Assisted Hydrogen Bonding in the hydrogen bonded chains of backbone amides of protein secondary structures such as beta sheets and alpha helices is determined by amide resonance. Variation in amide resonance is the means by which the hydrogen bonding in these chains is cooperative. Amide carbonyl orbitals are revealed by Natural Bond Orbital, NBO, analysis to substantially maintain sigma/pi separation in the presence of torsional hyperconjugative interactions with wavefunction methods but not with established Density Functional Theory, DFT, methods. This DFT error is most pronounced with small basis sets such as are used with DFT for proteins to reduce the basis function count. This error disturbs calculation of a range of amide donor-acceptor and steric interactions. This finding has important implications for the selection of electronic structure methods and basis sets for protein calculations. For example, great caution is needed in interpreting the results of applying established DFT methods to proteins containing any beta sheets. We recommend that every protein DFT calculation be accompanied by NBO assessment of maintenance of amide carbonyl sigma/pi separation and absence of carbonyl bond bending. Further, we propose that these metrics be standard benchmarks of electronic structure methods and basis sets.

physics.chem-ph↗

arXiv2016

Do cooperative cycles of hydrogen bonding exist in proteins?

The closure of cooperative chains of Hydrogen Bonding, HB, to form cycles can enhance cooperativity. Cycles of charge transfer can balance charge into and out of every site, eliminating the charge build-up that limits the cooperativity of open unidirectional cooperative chains. If cycles of cooperative HB exist in proteins, these could be expected to be significant in protein structure and function in ways described below. We find no mention of an example of this kind of cycle in the literature. We investigate whether cooperative HB cycles not traversing solvent, ligand or modified residues occur in proteins by means including search of Nuclear Magnetic Resonance spectroscopy entries of the Protein Data Bank. For the direct interactions of inter-amide HB, when the energy associated with Natural Bond Orbital, NBO, steric exchange is deducted from that of NBO donor-acceptor interactions, the result is close to zero, so that HB is not primarily due to the sum of direct inter-amide NBO interactions. The NBO binding energy is primarily associated with the increase in resonance of the amides, a consequence of which is that the majority of the NBO binding energy is susceptible to variation by electrostatic field with component parallel or antiparallel to an amide C-N bond. The question of what geometry most favours HB in amides is revisited with emphasis on the inequivalence of amide/carbonyl oxygen lone pairs. A possible avenue for the design of HB-chaining polymers with improved stability is discussed.

physics.chem-ph↗

arXiv2016

Variation of protein backbone amide resonance by electrostatic field

Amide resonance is found to be sensitive to electrostatic field with component parallel or antiparallel to the amide C-N bond, an effect we refer to here as EVPR-CN. EVPR-CN is linear and without threshold in the biologically plausible electrostatic field range -0.005 to 0.005 au. Variation of amide resonance varies Resonance-Assisted Hydrogen Bonding such as occurs in the hydrogen bonded chains of backbone amides of protein secondary structures such as beta sheets and alpha helices, varying the stability of these structures. The electrostatic properties including permittivity of amino acid residue sidegroups influence the electrostatic field component parallel or antiparallel to the C-N bond of each amide, giving a novel relationship between residue sequence and protein structure. Additionally, a backbone-based theory of protein folding which includes this effect is presented in Section 8.4. The significance of EVPR-CN relative to other factors in protein folding depends on field C-N component at each backbone amide at a given time. Calculation indicates that backbone amides do not occupy an intrinsically electrostatically-protected niche. We propose that EVPR-CN warrants investigation in any study of stable protein structure or protein folding pathway. EVPR-CN is somewhat associated with hydrophobia, since hydrophobia creates low permittivity environments. EVPR-CN is more directionally and hence structurally specific than hydrophobia. Hypotheses concerning the stability of beta sheets and amyloid fibrils and of protein complexation and molecular chaperone function are offered. An analogous effect in nitrogenous base pairing is proposed. EVPR-CN is energetically significant in biologically plausible electrostatic fields even without considering a hydrogen bonding context, and a hypothesis concerning the stability of polyproline helices types I and II is offered.

physics.chem-ph↗