Research Projects

Biomolecules undergo constant structural changes as they perform their functions. These changes range from small fluctuations of ligands bound tightly to a receptor, to larger but transient breathing events, and even adoption of completely different tertiary structures as occurs during protein folding. In the Simmerling group, we are interested in gaining insight into the biophysics of these changes, the interactions that drive them, and how they are modified in cases of disease or drug resistance.

Since most experimental techniques provide averages over time and/or macroscopic numbers of molecules, we develop and use a wide range of computer simulation methods to model these systems and understand the coupling between structure, energy, and dynamics. Each of our projects is closely coupled to experimental work by our collaborators.

How do coronaviruses use the spike protein to infect host cells?

Coronaviruses cause multiple human diseases, such as COVID-19.

We aim to understand how the spike protein on the surface of coronaviruses changes shape as it interacts with receptors on the host cell, allowing the virus to gain entry into and infect the host.

How do proteins recognize DNA?

Proteins are responsible for repair and replication of DNA. How does a protein locate and recognize a specific DNA sequence among the vast amount of DNA present in the cell? Our research explores the interaction of proteins with DNA.

Development of the Amber simulation software

Professor Simmerling is part of the leadership team for the widely-used Amber molecular simulation software, used in thousands of labs worldwide. Our main contributions to Amber include development of improved conformational sampling algorithms, fast implicit solvent methods, and implementation of our “SB” force fields (such as ff99SB, ff14SB and ff19SB).

New versions of Amber/AmberTools are released annually, with the current version being Amber 22 (with the cover image designed by Simmerling Lab member Lucy Fallon, based on her research). More information about Amber can be found at www.ambermd.org.

More accurate Force fields and solvent models

The quality of simulation results depends strongly on the ability of the underlying energy function (“force field”) to accurately model physical interactions. These force fields are the core of modern simulation software. Our team creates the widely-used “SB” force fields (where SB stands for the “Stony Brook” energy functions), with a particular emphasis on improving the physics-based protein models. Our three most recent force fields (ff99SB, ff14SB, and ff19SB) have over 7000 citations combined.

Conformational Sampling methods

In addition to force field accuracy, a major challenge in simulation of complex biomolecules is the slow dynamics of these systems, with timescales that are often longer than can be simulated on affordable computers. We develop new methods to improve sampling, providing reproducible results for complex dynamics.