DETERMINATION OF 3D STRUCTURE OF GAG POLY PROTEIN ISOLATE 90CF056 OF HIV TYPE 1 BY HIDDEN MARKOV MODEL AND NEURAL NETWORKS A POSSIBLE DRUG TARGET Original Article UNDETY BENJAMIN JASON 1 , DANIEL ALEX ANAND 2 1 Department of Bioinformatics, Sathyabama University, Chennai, Tamilnadu, India, 2 Department of Biomedical Engineering, Sathyabama University, Chennai,Tamilnadu, India. Email: ubjason@gmail.com Received: 01 Jul 2014 Revised and Accepted: 05 Aug 2014 ABSTRACT Introduction: The study of understanding the structural and molecular conservation of HIV-1 Gag function has revealed a number of potential Gag- related targets for possible therapeutic intervention. In this study, we emphasize that our current understanding of HIV-1 Gag poly protein suggest some approaches to be as a target for novel drugs. Objective: The functional conservation of HIV-1 Gag indicates rational drug design taking Gag as he drug target 1 Methods: The crystal structure of Gag poly-protein is unavailable. The templates similar are much smaller in size and thus ab-initio method is applied to determine the three dimentional structure of gag poly-protein. The value given in the program is an approximation of the probability as provided by the software with neural networks. The predictions are designed to be limited, to a score .HIV-1 may be blocked by targeting gag poly protein. This could proffer new scheme for novel drug classes that could complement current HIV-1 treatment options. >=.18 which is actually an approximation of the probability. The predictor is an artificial neural network. NN: Inputs indicates inclusion of separation and sequence length, e-value statistic which are based on mutual information values, a statistic based on propensity of residues in contact with each other. Results: The local structure predictions are performed with neural networks for several different local structure alphabets, and hidden Markov models are created. Conclusion: The complete three-dimensional model of the Gag poly protein is constructed by fold recognition and alignment to proteins in the Protein Data Bank is done. Keywords: HMM, Gag poly-protein, Neural networks. INTRODUCTION HIV-1 which causes AIDS is a retrovirus in genus Lentiviridae. HIV-1 is an enveloped virus and it encodes two envelope (Env) glycoproteins, they are surface (SU) glycoprotein gp120 and a transmembrane (TM) glycoprotein gp41. The gene of HIV-1, Gag encodes four major proteins, they are matrix (MA), capsid (CA), nucleocapsid (NC), and p6—and the pol-encoded enzymes protease (PR), reverse transcriptase (RT), and integrase (IN). The HIV-1 start off with the binding of gp120 to target cell plasma membrane [1-4]. The principal binding site of the receptor for HIV-1 is CD4. The binding of gp120 to CD4 and co-receptor commences conformational changes in gp41, thereby directs to the fusion of the viral envelope and the target cell membrane and entry of the viral core into the host cell cytoplasm. Latest works on HIV-1 suggests that HIV-1 entry is possible even in a low-pH endosomal compartment after receptor-mediated endocytosis [5].Once the virion enters into the cytosol, the Env glycoproteins and the lipid- associated MA protein dissociate from the incoming particle at the membrane, and the poorly understood process of uncoating is initiated. The gag-pol enzymes RT and IN, along with NC protein, remain in close association with the viral RNA as it is converted to double-stranded DNA by RT-catalyzed reverse transcription [6]. NC acts as a nucleic acid chaperone at multiple repeated steps during reverse transcription for the conversion of RNA to DNA [7]. The protein Vpr is a component of the reverse transcription complex. The process of reverse transcription and uncoating looks to be temporally linked,[8] and it is obvious that some host restriction factors that block early post entry steps in the viral replication cycle target CA.[9,10] The newly reverse transcribed viral DNA is translocated to the nucleus in a structure known as the preintegration complex (PIC). The process of nuclear import remains not understood completely; however, the role for CA in this process [11, 12]indicates that some CA protein may remain associated with the viral nucleoprotein complex as it traffics to the nuclear pore. Reaching inside the nucleus, the double-stranded viral DNA integrates into the target cell genome through the action of the IN enzyme.[13]The integrated viral DNA works as the template for transcription from the viral promoter in the 5’ long terminal repeat (LTR) to produce the spliced viral mRNAs and full-length genomic RNAs; these are transferred out of the nucleus via the action of the Rev protein. The Gag proteins are translated from full-length message as a polyprotein precursor which contains MA, CA, NC, and p6 domains along with other two spacer peptides, SP1 and SP2.[15] During the process of translation of Gag precursor, known as Pr55 Gag , an occasional 1 ribosomal frame shift leads to the production of a GagPol precursor protein (Pr160 GagPol ), the abundance of which is approximately 5% that of Pr55 Gag . The Gag and GagPol precursor polyproteins are transported to the plasma membrane, where they assemble and incorporate the viral Env glycoproteins. The membrane targeting Gag and GagPol is regulated by the MA domain, plays an important role in the incorporation of the viral Env glyco proteins. This assembly identified in cholesterol rich membrane microdomains (lipid rafts) through direct interactions between MA and the phospholipid phospha tidylinositol-4, 5-bisphosphate [PI(4,5)P2]. [17] The Gag gene of HIV-1 expressed MA (p17),CA (p24),SP1 (p2),NC (p7), SP2 (p1) and P6. HIV p6 is a 6 kDa polypeptide on the N- terminal of the Gag polyprotein. It inducts cellular proteins Tsg101 (a component of ESCRT-1) and Alix to initiate virus particle budding from the plasma membrane. Gag proteins are plays vital role in virus assembly, release, maturation and function in the establishment of a productive HIV 1. Though they play vital role throughout the replication cycle, there are no drugs targeting Gag poly protein. Interactions within the CA domain of Gag regulate the Gag assembly process. International Journal of Pharmacy and Pharmaceutical Sciences ISSN- 0975-1491 Vol 6, Issue 8, 2014 Innovare Academic Sciences