Cell Biochem Biophys DOI 10.1007/s12013-017-0786-5 ORIGINAL PAPER Identifying the Interaction of Vancomycin With Novel pH- Responsive Lipids as Antibacterial Biomaterials Via Accelerated Molecular Dynamics and Binding Free Energy Calculations Shaimaa Ahmed 1 ● Suresh B. Vepuri 1 ● Mahantesh Jadhav 1 ● Rahul S. Kalhapure 1 ● Thirumala Govender 1 Received: 20 December 2016 / Accepted: 21 February 2017 © Springer Science+Business Media New York 2017 Abstract Nano-drug delivery systems have proven to be an efficient formulation tool to overcome the challenges with current antibiotics therapy and resistance. A series of pH- responsive lipid molecules were designed and synthesized for future liposomal formulation as a nano-drug delivery system for vancomycin at the infection site. The structures of these lipids differ from each other in respect of hydro- carbon tails: Lipid1, 2, 3 and 4 have stearic, oleic, linoleic, and linolenic acid hydrocarbon chains, respectively. The impact of variation in the hydrocarbon chain in the lipid structure on drug encapsulation and release profile, as well as mode of drug interaction, was investigated using mole- cular modeling analyses. A wide range of computational tools, including accelerated molecular dynamics, normal molecular dynamics, binding free energy calculations and principle component analysis, were applied to provide comprehensive insight into the interaction landscape between vancomycin and the designed lipid molecules. Interestingly, both MM-GBSA and MM-PBSA binding affinity calculations using normal molecular dynamics and accelerated molecular dynamics trajectories showed a very consistent trend, where the order of binding affinity towards vancomycin was lipid4 > lipid1 > lipid2 > lipid3. From both normal molecular dynamics and accelerated molecular dynamics, the interaction of lipid3 with vancomycin is demonstrated to be the weakest (ΔG binding = -2.17 and -11.57, for normal molecular dynamics and accelerated molecular dynamics, respectively) when compared to other complexes. We believe that the degree of unsaturation of the hydrocarbon chain in the lipid molecules may impact on the overall conformational behavior, interaction mode and encapsulation (wrapping) of the lipid molecules around the vancomycin molecule. This thorough computational ana- lysis prior to the experimental investigation is a valuable approach to guide for predicting the encapsulation ability, drug release and further development of novel liposome- based pH-responsive nano-drug delivery system with refined structural and chemical features of potential lipid molecule for formulation development. Keywords pH-responsive lipids ● Liposomes ● Nano-drug delivery systems (NDDS) ● Vancomycin ● Molecular dynamics ● Binding affinity calculations Introduction Vancomycin (VCM) is a glycopeptide antibiotic used to treat infections caused by gram-positive bacteria, including those that are not responsive to other antibiotics. In parti- cular, VCM is used as a last resort to treat serious infections caused by bacteria resistant to penicillin’s, for example, methicillin-resistant Staphylococcus aureus (MRSA). However, VCM efficacy is being affected due to its excess and long-term use, while the rising prevalence of MRSA increases the possibility of VCM resistant S. aureus (VRSA), which is just as deadly as MRSA but more diffi- cult to treat [1, 2]. S. aureus, MRSA, and VRSA are organisms of current concern in developing and developed countries [3]. Although new antibiotics are being investi- gated to overcome antibiotic resistance, very few new drugs * Thirumala Govender govenderth@ukzn.ac.za 1 Discipline of Pharmaceutical Sciences, School of Health Sciences, University of KwaZulu-Natal, Private Bag X54001, Durban 4000, South Africa