SECTION A
Molecules based on the motif in Figure 1A(See Supplementary Information), are referred to as “Hamilton clefts” (HC).They have been found to bind to barbiturates and related molecules, labelled B1 to B7, in solution(See Supplementary Information, Figure 1B). The concentration of the bound HC-Bncomplex can be determined as can the relative strength of the binding between the HC and the molecule. (Note: the exact method to determine the experimental binding energy is not relevant here and no further information is required).For the HC where X = Y = CH2, experimental measurements of the relative binding strengths of B1-B5 have been determined using CHCl3as the solvent (see Supplementary Information Table 1A).Devise a forcefield-based computational chemistry study to investigate the binding of molecules B1to B7to the HC. Note you are not expected to perform any calculationsbut are encouraged to add figures to your report to illustrate your answer.Your answer must include a discussion of how to determine the most likely geometries of the isolated and bound molecules, includingany influence of the solvent and how the binding mechanism might change with temperature. Methodologies should not be described in detail, but your answer shouldhighlight any advantagesor disadvantagesof particular methods. Forcefield choice should be mentioned (you are not expected to select a specificforcefield, rather identify what the forcefield should be capable of describing). You should discuss how tocompare the computational results to the experimental datagiven (Table 1A).How would youexplain and correct for any anomalies? What additional information would the calculations provide toenhance understanding of the observations?[20 marks]When the solvent was changed to CH3CN, the relative binding “strength”of phenobarbitalto the HCwas reduced by a factor of 1000. Suggest a rapid computational investigation (based on what you have determined for the previous part) that might confirm that this measurement is not erroneous.[5 marks]It has been proposed that the binding of the HC can be enhanced by linkingthe two arms of the cleft together,as illustrated schematically in Supplementary Information Figure 1C. Suggest how you might identify computationally a suitable linking unit (L) to allow the selective binding of B6 and B7 (over B1 to B5) and how you would be able to demonstrate (computationally) how the linkedand original HC differ when binding to these two molecules. [5 marks]Your answer must not exceed two pages.
SECTION B
The heterocyclic molecule A is of interest for applications in organic light-emitting diodes. In order to better understand its properties experimentalists may wish to know:1.Atomic co-ordinates of its ground state geometry2.Energies of its low-lying electronically excited states3.Ionizationenergy and electron affinity4.Orbital energies in order to construct a molecular orbital (MO) diagram.5.A qualitative model to describe the orbital structure of its HOMO and LUMO.Describe what computational methods could be used to compute the above properties. Your discussion should include the advantages, disadvantages and limitations (if applicable) of the methods you propose, including (where appropriate) basis sets. You should also give a qualitative indication of which of the properties in 1-5 above are likely to be the most computationally demanding to compute, and which have lowest computational cost.You are not required to undertake any quantum mechanical calculations.[30 marks]Your answer must not exceed two pages.NHNNA
SECTION C
DNA nanopores are synthetic analogues of biological transmembrane protein pores, whichhave been designed for applications in single-molecule sensing and drug delivery. The behaviour of novel DNA nanostructures in the presence of lipid membranes is difficult to predict due to their high charge density and the flexibility of DNA. Describe a protocol for simulating a large heterogeneous DNA nanopore/membrane system, and discuss the structural features of the nanopore that could be characterised at different stages of the simulation protocol. Make use of figures provided in the Supplementary Information as you deem appropriate. Your answer should include:
•A description of the appropriate force-fields for these simulations, and a short summary of their advantages and disadvantages. [9marks]
•The function of the DNA nanopore in drug delivery and single-molecule sensing systems, and how the structural properties of the nanopores influence their functional propertiesindrugdelivery and small molecule sensingapplications.[9marks]
•A discussion of the difficulties that are commonly encountered when simulating DNA and where specifically they arise, and the limitations these difficulties impose on the kind of structural informationthat may be obtained. [6marks]•How might these limitations be circumvented?