Alexander MacKerell

Weber Group





  • Ph.D., Biochemistry, Rutgers University, 1985
  • B.S., Chemistry, University of Hawaii, 1981
  • A.S., Biology, Gloucester County College, 1979

Subsequent training involved postdoctoral fellowships in the Department of Medical Biophysics, Karolinska Intitutet, Stockholm, Sweden in experimental and theoretical biophysics and in the Department of Chemistry, Harvard University in theoretical chemistry. 


Dr. Alexander MacKerell’s research involves the development and application of computational methods to investigate the relationships of structure and dynamics to function in a range of biological and chemical systems. These efforts include empirical force field development, implementation of novel sampling methodologies, understanding the physical forces driving the structure and dynamics of proteins, nucleic acids, and carbohydrates, and computer-aided drug design (CADD) studies and methodology development. The MacKerell lab works closely with experimentalists in the area of drug development to provide detailed interpretation of experimental data while simultaneously refining and developing novel theoretical approaches.

The MacKerell lab is responsible for developing and maintaining the empirical force fields used in a number of simulation packages including the program CHARMM (Chemistry at HARvard Macromolecular Mechanics). CADD methodologies developed in the MacKerell lab include SILCS (Site-Identification by Ligand Competitive Saturation) and CSP (Conformationally Sampled Pharmacophore).

The Drude-2013 force field predicts differences in the X-ray scattering spectra of DNA duplex conformation in different environmental conditions, results that are not observed with the additive CHARMM36 force field (Savelyev and MacKerell, 2015, J Phys Chem Lett).
SILCS FragMaps overlaid on an inhibitor of the protein Factor Xa.  The FragMaps may be used to facilitate ligand design.


A central focus of Dr. MacKerell’s group is the continued development and extension of empirical force fields and enhanced sampling methods for use in the simulation of biological macromolecules. Such simulations are important in advancing the understanding of how intrinsic characteristics and environmental conditions contribute to the conformational properties of proteins, nucleic acids, lipids, carbohydrates, and small molecules.

In addition to widely used additive force fields, the MacKerell lab developed a polarizable force field for biomolecules, based on a classical Drude oscillator model. Drude-2013 extends the capabilities of molecular dynamics simulations, as in the example shown in the graph to the right.

CADD is a powerful tool that must contend with both the large conformational space of flexible macromolecular drug targets like proteins and the large chemical space of potential drug-like molecules to be screened against the target. Work in the MacKerell lab seeks to address these challenges with the development of new methodologies. For example, the SILCS (Site Identification by Ligand Competitive Saturation) methodology may be used for lead compound identification and optimization, evaluation of protein-protein interactions, and optimization of formulation via rational selection of excipients and buffer.

Image of the HIV envelope trimer including both the glycans and proteins obtained from an enhanced sampling MD simulation.

Additional activities in the MacKerell lab include structure-function studies of carbohydrates, proteins, and nucleic acids. Recently, the lab used enhanced sampling methods to explore the conformational heterogeneity HIV envelope protein glycans (Yang et al. 2017, Scientific Reports), resulting in the identification of novel glycan-antibody interactions that may play a role in neutralizing the virus.  See for additional information on the MacKerell lab.

Combining SILCS and Artificial Intelligence for High-Throughput Prediction of the Passive Permeability of Drug Molecules.
Nitro-benzylideneoxymorphone, a bifunctional mu and delta opioid receptor ligand with high mu opioid receptor efficacy.
Identification of a novel transport system in Borrelia burgdorferi that links the inner and outer membranes.
Influence of Mg2+ Distribution on the Stability of Folded States of the Twister Ribozyme Revealed Using Grand Canonical Monte Carlo and Generative Deep Learning Enhanced Sampling.
Integrated Covalent Drug Design Workflow Using Site Identification by Ligand Competitive Saturation.
GPU-specific algorithms for improved solute sampling in grand canonical Monte Carlo simulations.
Drude Polarizable Lipid Force Field with Explicit Treatment of Long-Range Dispersion: Parametrization and Validation for Saturated and Monounsaturated Zwitterionic Lipids.
Site Identification by Ligand Competitive Saturation-Biologics Approach for Structure-Based Protein Charge Prediction.
Structure-Based Design of Potent Iminosugar Inhibitors of Endoplasmic Reticulum α-Glucosidase I with Anti-SARS-CoV-2 Activity.
hERG Blockade Prediction by Combining Site Identification by Ligand Competitive Saturation and Physicochemical Properties.
Glycosidic α-linked mannopyranose disaccharides: an NMR spectroscopy and molecular dynamics simulation study employing additive and Drude polarizable force fields.
In silico identification of a β2-adrenoceptor allosteric site that selectively augments canonical β2AR-Gs signaling and function.
Computer-Aided Drug Design: An Update.
Scaffold hopping from indoles to indazoles yields dual MCL-1/BCL-2 inhibitors from MCL-1 selective leads.
Extension of the CHARMM Classical Drude Polarizable Force Field to N- and O-Linked Glycopeptides and Glycoproteins.
Spatial requirements for ITAM signaling in an intracellular natural killer cell model membrane.
Preserving the Integrity of Empirical Force Fields.
SILCS-RNA: Toward a Structure-Based Drug Design Approach for Targeting RNAs with Small Molecules.
Accurate modeling of RNA hairpins through the explicit treatment of electronic polarizability with the classical Drude oscillator force field.
In Silico Identification of a β2 Adrenergic Receptor Allosteric Site that Selectively Augments Canonical β2 AR-Gs Signaling and Function.