ORIGINAL PAPER Study of the betulin molecule in a water environment; ab initio and molecular simulation calculations Miroslav Pospíšil & Petr Kovář & Robert Vácha & Michal Svoboda Received: 1 September 2010 / Accepted: 22 March 2011 / Published online: 3 May 2011 # Springer-Verlag 2011 Abstract Ab initio and molecular simulation methods were used in calculations of the neutral individual betulin molecule, and molecular simulations were used to optimize the betulin molecule immersed in various amounts of water. Individual betulin was optimized in different force fields to find the one exhibiting best agreement with ab initio calculations obtained in the Gaussian03 program. Dihedral torsions of active groups of betulin were determined for both procedures, and related calculated structures were compared successfully. The selected force field was used for subsequent optimization of betulin in a water environ- ment, and a conformational search was performed using quench molecular dynamics. The total energies of betulin and its interactions in water bulk were calculated, and the influence of water on betulin structure was investigated. Keyword Betulin . Molecular simulation . Ab initio calculation . Hydrogen bond Introduction Betulin has long been investigated by research scientists due to its anticancer properties. Betulin and some of its transformation products were first isolated from Maine white birch, Betula papyrifera, in the 1950s. Subsequently, betulinic acid was found to be uniquely effective against various types of human melanoma. This led to a search for other anticancer drugs from natural sources such as plants and marine organisms. As a result, new anticancer drugs like actidione (cycloheximide), carminomycin and bufalin were discovered and synthesized. Such synthesized anti- cancer substances followed known biosynthetic lead struc- tures (2-haloethylamines, diazoketone groups). By contrast, marine invertebrates are a remarkable source of antineo- plastic (cytostatic) substances and anticancer drugs with completely novel structural types. These newly discovered anticancer substances came in different modifications like cephalostatin, spongistatin, halistatin, dolastatin, bryostatin, etc. [1]. Betulin and its derivatives belong to the group of natural lupane compounds. The natural source of betulin is European white birch (Betula pendula Roth.), which is found mostly in Russia. Naturally occurring betulin can be isolated from many different sources such as trees {Quercus suber L [2], Acacia mellifera bark traditionally used in African medicine [3], Celtis philippinensis Blanco (Indonesia) [4], aerial parts of Asteracantha longifolia Nees (India) [5], aerial parts of Coccoloba acrostichoides Cham (Brazil) [6], Betula papyfera bark} by vacuum and atmospheric sublimation, with the optimal conditions for extraction being 3.3 kPa and isothermal heating at 200°C [7]. Synthesis of betulin and its derivatives is in great demand due to its biological activity. Betulin and its esters can inhibit growth of cancer cells and prevent tumor development, suppress HSV-1 and HSV-2 replication, cause 50% inhibition of HIV-1 replication as an active anti-HIV agent, and exhibit some antitubercular activity [8–11]. Betulin derivatives and isomers often have better desirable properties for the pharmaceutical industry than betulin M. Pospíšil (*) : P. Kovář Faculty of Mathematics and Physics, Charles University in Prague, Ke Karlovu 3, 12116 Prague 2, Czech Republic e-mail: pospisil@karlov.mff.cuni.cz M. Pospíšil : R. Vácha : M. Svoboda I.Q.A., Jindřicha Plachty 16, 15000 Prague 5, Czech Republic J Mol Model (2012) 18:367–376 DOI 10.1007/s00894-011-1055-y