CHEM 408 – Sp06 2/20/2006 1Assignment #6 – MM and More Complex Molecules Due: Friday March 3, 2006 Reading: F.-G. Klärner and B. Kahlert, “Molecular Tweezers and Clips as Synthetic Receptors. Molecular Recognition and Dynamics in Receptor-Substrate Complexes”, Acc. Chem. Res. 36, 919 (2003). _____________________________________________________________________________________ 1. (20 points) Read the review by Klärner & Kahlert and answer the following questions: (a) Discuss what is meant by the term “molecular recognition” and how it relates to the authors’ motivations for synthesizing and studying molecular “tweezers” and “clips”. (b) Schemes 1 and 2 illustrate a variety of other systems that have been used in similar studies. What (if any) advantage do the authors’ compounds have for studies of molecular recognition? (c) What types of experimental data are available to characterize the host molecules and their interactions with guest species? (d) What (experimental) evidence is there that electrostatic interactions play an important role in the host-guest binding of these complexes? (e) What role has computational chemistry, especially molecular mechanics, played in the authors work? Note on “EPS”s: The pretty colored pictures shown on p. 930 of this article (and appended to this assignment), which the authors term “Electrostatic Potential Surfaces” (EPS) are one way of representing the electrostatic potential surrounding a molecule. The information is of the same sort as we examined in WS#3 -- the value of the electrostatic potential at various points in space in the vicinity of a molecule. The present representation is what is termed a mapped isosurface. An isosurface is a surface over which some particular molecular property takes on a specific constant value. In the present case, the isosurface is chosen to depict the approximate size and shape of the molecule as defined by a specific (but unspecified) value of the electron density. Onto this isosurface the electrostatic potential is mapped by a color coding that represents the value of the electrostatic potential at each point on the surface. The “potential” here is given in energy units. As in WS#3 these energies are energies that would be felt by a unit positive charge at each point. (We will study such surfaces in more detail later.) _____________________________________________________________________________________ 2. (60 points) Use the molecular mechanics algorithms available in HyperChem to explore the receptor + substrate interactions in the systems described by Klärner & Kahlert. For this purpose use the MM+ force field supplemented by atomic charges obtained as described below. It is completely up to you what calculations to do. You will be graded on the basis of the quality of the insights your calculations provide on one or more of the following topics: (i) the accuracy of MM+ in this context, (ii) the us of MM in supporting the authors’ interpretation of experimental data, (iii) the relevance of various types of interactions to the binding in these systems, (iv) related receptor or donor systems that might be synthesized to better understand these systems. This list is not exhaustive, I provide it only to help get you thinking about possibilities. I’d be happy to discuss ideas with you, but I want you to choose what questions to ask and how to answer them. Turn in your results with appropriate tables, figures and commentary that make your motivation and results clear. Notes: When making comparisons to experimental data, keep in mind (and discuss if it is relevant) the likely differences between isolated receptor + substrate complexes and these molecules in solution or in the crystalline state.CHEM 408 – Sp06 2/20/2006 2The receptors used here are more complicated molecules than those we’ve studied thus far. For this reason, they will take longer and be harder to geometry optimize. You may need to increase your gradient tolerance for geometry optimization compared to what was possible for smaller systems, but keep the tolerance as small as possible to achieve convergence. Report the tolerance values you use where relevant. Also be aware that there may be many local minima in the receptor + substrate potential energy surface. You will need to start minimizations from several locations in order to determine the likely global minimum. Obtaining Charges: The simplest way to obtain atomic charges for these calculations is to use semi-empirical electronic structure methods. We’ve not yet talked about such methods, but we will soon. After creating the molecule of interest and optimizing its geometry in MM+ do a single-point calculation using the AM1 semi-empirical method: /Setup/Semi-empirical/AM1/OK /Calculate/Single_Point Doing so will provide atomic charges for all atoms within the molecule. When you change your method back to molecular mechanics and switch to the use of atomic charges rather than bond dipoles /Setup/Molecular_Mechanics/MM+/Options/Atomic_Charges/OK/OK these charges will be remain available for use. You should check that charges are properly applied (/Display/Labels/Charges). I recommend first going through this exercise with the molecule benzene in order to see what sorts of charges are generated. Do they seem sensible? Pretty Pictures: Mainly for your own enjoyment and edification, you can also make mapped isosurface plots of the electrostatic potential of the sort discussed above. To do so, after generating charges with the AM1 method, under the /Compute/Plot_Molecular_Properties menu, use the commands: /IsoSurface_Grid/Medium - set resolution /Isosurface_Rendering/Total_charge_density = 0.01/OK - set value of electron density /Molecular_Properties/Representation = 3D Mapped Isosurface/OK - choose isosurface (ESP) _____________________________________________________________________________________ 3. (Extra Credit; 20 points) Even in the absence of real computations, programs like HyperChem serve the important function of enabling one to visualize complex molecules, an aspect of molecular modeling that is especially important in the case of biological molecules. This problem provides a brief glimpse of biomolecule visualization, which we won’t have time to address otherwise. On the following page is a rendition of a protein molecule called human serum albumin (HSA)