SMALL MOLECULE COMPUTATIONAL CHEMISTRY for COMPUTATIONAL BIOLOGY and MACROMOLECULAR MODELING Thursday, July 23, S.Aravamudhan ICETCS, CUG March 14-15, Stay connected to the internet through out this presentation Organizers acceptance for participation International Conference on Emerging Trends in Chemical Sciences Central University of Gujarat, Gandhinagar

Coarse-Grained (Multiscale) Simulations in Studies of Biophysical and Chemical Systems Abstract Recent years have witnessed an explosion in computational power, leading to attempts to model ever more complex systems. Nevertheless, there remain cases for which the use of brute-force computer simulations is clearly not the solution. In such cases, great benefit can be obtained from the use of physically sound simplifications………………. Annu. Rev. Phys. Chem :41–64 Computer modeling of the function of macromolecules and related systems presents a problem of enormous complexity. Although available computer power has increased rapidly, there are, nevertheless, still many cases for which the use of brute-force simulations is clearly not the best approach. Furthermore, there exist many systems whose nature was correctly elucidated even before the emergence of the current level of computing power…………... …………………………….Obviously, this has enormous difficulties. However, there also exist far less dramatic examples of cases in which one cannot (and perhaps should not) progress without the use of a simplified model, and, in fact, recent years have witnessed a growing appreciation of the fact that the simulation of complex systems, and, in particular, the modeling of biological function, can greatly benefit from physically sound simplifications. 1. INTRODUCTION Workshop on Modeling Biological Systems Thursday, July 23, S.Aravamudhan ICETCS, CUG March 14-15,2013 Download Full article

H 2 N CHR COOH, the nonionic neutral form does not find much mention: Can there be equilibrium between zwitterion and the nonionic form at neutral pH? Acidic Alkaline Why only the zwitterions is a dipolar ion and not the other ions? Neutral water molecule has a permanent dipole moment and water is a polar solvent Beginning with the contents of TEXTBOOK on ORGANIC CHEMISTRY by Morrison and Boyd……….. Thursday, July 23, S.Aravamudhan ICETCS, CUG March 14-15,2013

| μ | = qd Sign convention for dipole has been reversed All atoms are neutral. Atoms covalently bonded in molecules are considered have the full share of the one of electron of the shared pair of electron hence such atoms are also neutral Partially covalent bonds between atoms cause partial charges to be located and these can give rise to dipole moments; Polar bonds Thursday, July 23, S.Aravamudhan ICETCS, CUG March 14-15,2013 Links below are for getting clarifications on the conventions

Thursday, July 23, 2015 S.Aravamudhan ICETCS, CUG March 14-15, Electric field : direction in which a positive charge would move in the region; from positive charge to the negative charge Material object is placed in this region (a dielectric material) then the field induces charges within the medium. The induced positive charge would be nearer to the (pre- existing) negative charge and at the other end the negative charge is induced. Such induced pair of opposite charges would have a strength and distance of separation; thus are said to be characterized by a dipole moment in the direction from induced negative charge to the positive charge. Dipole moment and the field are in the same direction and hence this is described by dipole moment aligning with the external field. - +

Nearly same energetic structures but widely varying dipole moment characteristics. Does this have a significance at any stage in modeling systems? To know the orientation of dipole moment of water molecule is simple enough but as the glycine molecule finds itself in varying environments it would not be all that simple to estimate its dipole moment. Thursday, July 23, S.Aravamudhan ICETCS, CUG March 14-15,2013 Maximum difference of 6.5 Kcals mole -1

Zwitterion/neut Nonionic/neut Zwitter ion is a case in which a full unit of positive charge and negative charge are located at different ends of the molecule and hence special reference as dipolar ion. Other categories are cation, anion or polar molecule where partial charges are created. Difference of about KCals per Mole Thursday, July 23, S.Aravamudhan ICETCS, CUG March 14-15,2013 The nonionic form is more stable. But in neutral pH, the zwitterionic form predominates. Indicates the importance of the stabilization by water medium. Click for computed results

Since the two neutral forms of the amino acid (Glycine) have small energy difference, if an input structure corresponds to the guessed structure for zwitter ionic form, using an abinitio QM method with STO 3G basis set, a ge4ometrical optimization invariably results in the nonionic neutral form. In all these what is the importance of Energy? And, When the structures are nearly of same energy, can electric dipole moment, be of any consideration? A few model situations for exemplifying the above consequences are included in the next slide. Thursday, July 23, S.Aravamudhan ICETCS, CUG March 14-15,2013 0_1_Gly_Movie_2.gif 0_2_MV_0_45.JPG

0_3_glyw_opt_movie.gif Glycine neutral nonionic str-3 & Water Note the dipole moment characteristics of these two molecules. When these two molecules are placed juxtaposed and subjected to optimization, what would be the consequence? During this process how would have the energy varied? 0_3_glyw_opt_movie.jpg The above optimization structure sequence displayed at a faster time scale 0_3_glyw_opt_movie_faster.gif 0_3_glyw_opt_movie_Wrotated.gif Hydrophilic? Hydrophobic? Thursday, July 23, S.Aravamudhan ICETCS, CUG March 14-15,2013 Water dipole rotated by 180 degrees.

Note the similar process sequentially when a zwitterion is placed with water molecule for a geometry optimization 0_4_glyzw-w.-opt-mov.gif Corresponding trends of variation in energy for the above sequence of structures 0_4_glyzw-w-opt-mov.jpg Thursday, July 23, S.Aravamudhan ICETCS, CUG March 14-15,2013 The way the theoretical calculations display the movement of water molecule in presence of glycine, could be the way a drug molecule moves towards the target macromolecule governed by electrical forces. If the small molecule moves so in a biological fluid medium, this would be similar to the way a ship would be moving in water current and gets docked at the port. Hence small molecule gets docked on the macromolecule for favorable interaction. This word has been used also while virtual computer aided screening and positioning the small molecule in the binding sitethis would be similar to the way a ship would be moving in water current and gets docked at the port

Spectroscopy can distinguish the cation, anion, neutral nonionic form and the neutral zwitter ionic forms. Computational (Quantum Chemical) softwares provide for calculations of these spectra theoretically and to compare with experimental results. A typical calculated results is displayable from the link below: 0_5_sapDnmr-ni-zw-persp.JPG Even if experimentally the spectra cannot be obtained for the variety of structures, calculated pattern and the partial charge distributions can give valuable information on the trends of electronic structure variations due to the interactions. This can be helpful in modeling the system appropriately for reaching an optimal solutions without too much of search. Thursday, July 23, S.Aravamudhan ICETCS, CUG March 14-15,2013

The link below is a reproduction from a book on Biological NMR. The experimental spectral trends have been reported. 0_6_exptal_spectral_trends.JPG 0_7_variation_NMR_forGOsequence.JPG A similar trend as above from computational software 0_8_glycine-isomers-water-GO-60pc.JPG 0_9_File3.pdf After this much of introduction to theoretical methods for spectroscopic manifestations during geometrical structure variations………………… Getting more information from cluster calculations Thursday, July 23, S.Aravamudhan ICETCS, CUG March 14-15,2013 On the role of water there are several publications from Theoretical Biologists who have investigated using quantum chemical methods. Some of these date back to s. These can be reviewed in the current scenario of Computational Chemistry……….

Thursday, July 23, 2015 S.Aravamudhan ICETCS, CUG March 14-15, If any problems are encountered while downloading the PowerPoint files, type in the URL: in the browser address bar and find the appropriate web folders and files. Click on this Hyperlink for NEXT TOPIC on Specific Interaction Water Amino acid