Practical computational toolkits for dendrimers and dendrons structure design

Dendrimers and dendrons offer an excellent platform for developing novel drug delivery systems and medicines. The rational design and further development of these repetitively branched systems are restricted by difficulties in scalable synthesis and structural determination, which can be overcome by judicious use of molecular modelling and molecular simulations. A major difficulty to utilise in silico studies to design dendrimers lies in the laborious generation of their structures. Current modelling tools utilise automated assembly of simpler dendrimers or the inefficient manual assembly of monomer precursors to generate more complicated dendrimer structures. Herein we describe two novel graphical user interface (GUI) toolkits written in Python that provide an improved degree of automation for rapid assembly of dendrimers and generation of their 2D and 3D structures. Our first toolkit uses the RDkit library, SMILES nomenclature of monomers and SMARTS reaction nomenclature to generate SMILES and mol files of dendrimers without 3D coordinates. These files are used for simple graphical representations and storing their structures in databases. The second toolkit assembles complex topology dendrimers from monomers to construct 3D dendrimer structures to be used as starting points for simulation using existing and widely available software and force fields. Both tools were validated for ease-of-use to prototype dendrimer structure and the second toolkit was especially relevant for dendrimers of high complexity and size.Peer reviewe

Molecular modeling to study dendrimers for biomedical applications

© 2014 by the authors; licensee MDPI; Basel; Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/4.0/). Date of Acceptance: 17/11/2014Molecular modeling techniques provide a powerful tool to study the properties of molecules and their interactions at the molecular level. The use of computational techniques to predict interaction patterns and molecular properties can inform the design of drug delivery systems and therapeutic agents. Dendrimers are hyperbranched macromolecular structures that comprise repetitive building blocks and have defined architecture and functionality. Their unique structural features can be exploited to design novel carriers for both therapeutic and diagnostic agents. Many studies have been performed to iteratively optimise the properties of dendrimers in solution as well as their interaction with drugs, nucleic acids, proteins and lipid membranes. Key features including dendrimer size and surface have been revealed that can be modified to increase their performance as drug carriers. Computational studies have supported experimental work by providing valuable insights about dendrimer structure and possible molecular interactions at the molecular level. The progress in computational simulation techniques and models provides a basis to improve our ability to better predict and understand the biological activities and interactions of dendrimers. This review will focus on the use of molecular modeling tools for the study and design of dendrimers, with particular emphasis on the efforts that have been made to improve the efficacy of this class of molecules in biomedical applications.Peer reviewedFinal Published versio

MOLECULAR DYNAMICS STUDIES OF BIOMIMETIC MEMBRANES

We have explored the conformational dynamics of the peptide-appended pillar[5]arene (PAP) channel in lipid and block copolymer (BCP) membranes through the use of molecular dynamics (MD) simulations. The novel polymeric structures trans-1,4-polybutadiene (PB), trans-1,4-polyisoprene (PI), and poly-2-methyl-2-oxazoline (PMOXA) were created and parameterized. These structures were then used to build and simulate pure PB12PEO9, PB23 PEO16 , PI12 PEO9 , and PI23PEO16 synthetic BCP membranes. In addition, simulations of the PAP channel inserted into lipid (POPC), PB12 PEO9 , and PB23PEO16 membranes were conducted. Results of simulations containing PAP suggest that the membrane environment can affect the channel dynamics and potentially its diffusive as well as transport characteristics. Next, we began to explore the microscopic structure of block copolymer membranes using coarse-grained methods. We tested original MARTINI force-field parameters by simulating the self-assembly of a POPC lipid bilayer. We then used the MARTINI force-field to build and simulate coarse-grained models of PB12PEO9. The original MARTINI force-field was unable to show the self-assembly of PB 12PEO9 and must therefore be further optimized to observe the desired behavior