SMALL MOLECULE COMPUTATIONAL CHEMISTRY for COMPUTATIONAL BIOLOGY and MACROMOLECULAR MODELING Saturday, June 04, S.Aravamudhan Workshop July 25-30, Stay connected to the internet through out this presentation Organizer’s acceptance for participation

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 Saturday, June 04, S.Aravamudhan Workshop July 25-30,2011 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……….. Saturday, June 04, S.Aravamudhan Workshop July 25-30,2011

| 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 Saturday, June 04, S.Aravamudhan Workshop July 25-30,2011 Links below are or getting clarifications on the conventions

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. Saturday, June 04, S.Aravamudhan Workshop July 25-30,2011 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 Saturday, June 04, S.Aravamudhan Workshop July 25-30,2011 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. Saturday, June 04, S.Aravamudhan Workshop July 25-30,2011

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? The above optimization structure sequence displayed at a faster time scale Hydrophilic? Hydrophobic? Saturday, June 04, S.Aravamudhan Workshop July 25-30,2011 Water dipole rotated by 180 degrees.

Note the similar process sequentially when a zwitterion is placed with water molecule for a geometry optimization Corresponding trends of variation in energy for the above sequence of structures Saturday, June 04, S.Aravamudhan Workshop July 25-30,2011 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 b e 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 b e 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: 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. Saturday, June 04, S.Aravamudhan Workshop July 25-30,2011

The link below is a reproduction from a book on Biological NMR. The experimental spectral trends have been reported. A similar trend as above from computational software After this much of introduction to theoretical methods for spectroscopic manifestations during geometrical structure variations………………… Getting more information from cluster calculations Saturday, June 04, S.Aravamudhan Workshop July 25-30,2011 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……….

Saturday, June 04, 2016 S.Aravamudhan Workshop July 25-30, Intermediate Results in Computational Biology: Can they be the Realities during Biological Processes? S. Aravamudhan Department of Chemistry North Eastern Hill University SHILLONG Meghalaya: INDIA This topic has been inspired by the current BIOLOGICAL applications of Magnetic Resonance Techniques (NMR in particular) and the advances in Computational Chemistry Context of my Contributions to IBS Meetings Abstract: Workshop on Modeling Biological Systems

Saturday, June 04, 2016 S.Aravamudhan Workshop July 25-30, 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.

Saturday, June 04, 2016 S.Aravamudhan Workshop July 25-30, Questions ; Comments ; Remarks Prof.S.Aravamudhan Phone: Department of Chemistry Mobile: North Eastern Hill University Shillong Meghalaya URL: A link to the facsimile of the participation certificate participation certificate