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David Gohara, Ph.D.

Adjunct Assistant Professor
Biochemistry and Molecular Biology


Investigation of macromolecular structure/function relationships using computer based approaches.

Research Highlights

This video shows a molecular dynamics simulation of the non-structural protein 3CD from poliovirus. It consists of two domains: 3C, a cysteine protease and 3D the RNA-dependent RNA Polymerase (larger domain). The MD technique used is RaMD-db. The initial portion of a molecular dynamics simulation of a small molecule prior to entering the membrane (POPC). Water molecules used in the simulation are not shown. In this video the serine protease thrombin undergoes a simple two state transition (green highlighted residue, W215). The first half of the animation simply shows a 360 degree view of the molecule. In the second half electrostatic visualization is turned on. Blue represents positive potential and red (very faint) negative. The two panels show a traditional molecular dynamics simulation vs one use a form of

Dynamics and Electrostatics

One of the biggest challenges in trying to understand how structure affects function is assessing energetic properties of macromolecules. In this regard, computational techniques can help provide insight into possible mechanisms of action. In many cases, these methods are complimentary to experimental methods and can be helpful in developing further experimentally testable hypotheses.

To the right are several simulations that were performed to better understand the roles that dynamics and electrostatics have in driving molecular interactions.

Conformational Sampling for Drug Discovery

A particularly interesting problem is generating conformational states that can then be used subsequently for in-silico docking. Molecular dynamics is a useful method for generating high probability cluster states. This is more important when only handful of structures are available for a given molecule. However, even in cases where a large number of structures are available, structural variation (in the dynamic sense)  may not be as readily observed (although probably exist outside the static crystal structure).

One such example are the trypsin-like family of serine proteases (e.g., thrombin). The image gallery below illustrates the point (open the gallery to for more details).

The Active Site Of The Serine Protease Thrombin. Residues That Form The Catalytic Triad Are Labeled, As Is Highly Conserved Tryptophan (W215). The Measure Of The Aperture Is The Key Indicator Used To Identify Which State The Enzyme Is In (open Vs Closed). In This Case It Is Open.

Thrombin Bound To The Irreversible Inhibitor PPACK.

In The Above Image A Sample Of Trypsin-like Serine Protease Structures, Taken From The PDB, Are Shown. Each Molecule Was Superpositioned, And In Each Case The Molecule Is In The Open Position.

Similar To The Previous Slide. In This Example The X-ray Crystal Structure Of Thrombin In The Collapsed State Is Shown In (red).

Histogram Of Aperature Distance. An Analysis Of Every Chain In All Deposited Trypsin-like Serine Proteases In The PDB (~2200) Reveals That The Vast Majority Of Structures Are In The Open State. This Remains True When Structures With A Molecule Or Other Component In The Active Site Are Filtered Out (not Shown).

Following Molecular Dynamics The States Of The Molecule Are Clustered. In This Case, The Top Five Major Populations Were Produced (out Of 10). The Image Above Shows The Superpositioning Of A Representative From Each Of The Five Major States. Each State Can Then Be Used For Docking Analysis. The Primary Purpose Of Which Is To Identify Molecules That Bind Specifically To A Single State.

Research Interests

My primary research these days focuses on the use of graphics processing units (GPUs) in scientific computations. Specifically the application of high performance computing for structural biology applications. Technologies such as CUDA, Stream and OpenCL have made accessing the processing power of the GPU much easier. OpenCL, an open specification, in particular, has been established as a standard for accessing not only GPUs but any hardware specific feature that possesses a programmable pipeline.


Costimulatory Effects of an Immunodominant Parasite Antigen Paradoxically Prevent Induction of Optimal CD8 T Cell Protective Immunity
Eickhoff CS, Zhang X, Vasconcelos JR, Motz RG, Sullivan NL, O’Shea K, Pozzi N, Gohara DW, Blase JR, Di Cera E and Hoft DF
Pubmed | PLoS Pathog.

Molecular Mechanisms of Enzyme Activation by Monovalent Cations
Gohara DW and Di Cera E
Pubmed | J. Biol. Chem.

Loop Electrostatics Asymmetry Modulates the Preexisting Conformational Equilibrium in Thrombin
Pozzi N, Zerbetto M, Acquasaliente L, Tescari S, Frezzato D, Polimeno A, Gohara DW, Di Cera E and De Filippis V
Pubmed | Biochemistry

Potassium and the K+/H+ Exchanger Kha1p Promote Binding of Copper to ApoFet3p Multi-copper Ferroxidase
Wu X, Kim H, Seravalli J, Barycki JJ, Hart PJ, Gohara DW, Di Cera E, Jung WH, Kosman DJ and Lee J
Pubmed | J. Biol. Chem.

Why Ser and not Thr brokers catalysis in the trypsin fold
Pelc LA, Chen Z, Gohara DW, Vogt AD, Pozzi N and Di Cera E
Pubmed | Biochemistry