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Studies of Protein Interactions and Knowledge-Based Drug Design: (A) The Electrostatic Nature of Recognition Between HIV-1 gp120 V3 Loop and Coreceptors CCR5/CXCR4, (B) Complement System Inhibition by Compstatin Family Peptides


Computational and experimental methods were used to understand (i) protein interactions involving the V3 loop of gp120 of HIV-1 with coreceptors in host cells and (ii) peptide analogs from the compstatin family to human C3. Computational methods, including molecular dynamics (MD) simulations and electrostatic calculations, provide quantitative predictions of dynamics and interactions at atomic resolution, while experimental methods, including surface plasmon resonance (SPR) and enzyme-linked immunosorbent assays (ELISA) are needed to confirm binding and inhibition.

HIV-1 entry into host cells is mediated by the interaction of the V3 loop of gp120 and coreceptors CCR5 or CXCR4 on host cell surfaces, with assistance of viral protein gp41 and cell receptor CD4. The mechanism of coreceptor selectivity is not well understood, given the sequence variability and structural flexibility of the V3 loop. Positive net charge is a persistent physicochemical property throughout HIV subtypes and has been recognized as an influencing factor for cell entry. Electrostatic analyses of V3 loop structures with consensus sequences from HIV subtypes, show similar electrostatic potential characteristics, irrespective of sequence variability. Charge and other sequence-based criteria were combined to develop a scheme for determining coreceptor selection. In addition, MD simulations provide insight into loop dynamics, indicating that persistent salt bridges contribute in keeping the two loop strands in proximity, therefore providing a charged scaffold for electrostatic interactions with coreceptors, irrespective of structural variability.

Compstatin family peptides are inhibitors of the complement system and potential drug candidates against autoimmune and inflammatory diseases. Compstatin analogs are cyclic peptides that inhibit cleavage of human C3, therefore preventing further complement system activation. Introduction of tryptophan residues at the termini resulted in potent analogs, but suffering from reduced solubility. To balance hydrophobicity (important for binding) and polarity (important for solubility), additional analogs were designed guided by MD simulation results of bound analogs to C3. New analogs with polar substitutions at the N-terminus, including dipeptide sequence extensions and use of methylated tryptophan residues, were experimentally tested with ELISAs, demonstrating comparable inhibition to that of known analogs, but with improved solubility.

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